leptin and Osteoarthritis

This study aimed to systemically review the evidence on the relationship between the circulating leptin levels and osteoarthritis (OA), and the association between leptin and leptin receptor (LEPR) polymorphisms and OA susceptibility.. To find relevant papers (up to February 2023) examining the association between circulating leptin levels, LEPR polymorphisms, and OA, the PUBMED, EMBASE, and Cochrane databases were searched. We performed a meta-analysis to examine the levels of synovial and serum/plasma leptin in OA patients compared with healthy controls, as well as the relationship between OA and LEPR polymorphisms.. Data from 15 investigations, totaling 2197 patients with OA and 2546 controls, were included in the meta-analysis. There were statistically significant differences in the levels of circulating leptin between the OA and control groups (standardized mean difference [SMD] 2.178, 95% confidence interval [CI] 1.208-3.139, P = 0.001). Leptin levels were also substantially greater in European, Asian, and Arab groups among OA patients. After adjusting for age, sex, and/or body mass index, the leptin levels of patients with OA were significantly higher. Similarly, regardless of sample size (n < 100 and n ≥ 100) or year of publication, leptin levels were considerably higher in the OA group. In addition, the synovial leptin level was greater in the OA group than in the control group (SMD 0.783; 95% CI 0.247-1.319, P = 0.004). In the LEPR rs1137101 polymorphism, the OA and AA genotypes were significantly associated (odds ratio 0.282, 95% CI 0.126-0.629, P = 0.002), according to the meta-analysis. Ethnic stratification revealed an association between OA and the LEPR rs1137101 AA genotype in Asian and Arab populations.. The results of this meta-analysis indicate that patients with OA had considerably greater levels of circulating leptin than did control individuals. In addition, synovial leptin levels were greater in OA patients than in healthy individuals, and the LEPR rs1137101 polymorphism was linked to an increased risk of developing OA. These results imply that leptin participates in the onset and progression of OA.

Topics: Genetic Predisposition to Disease; Genotype; Humans; Leptin; Osteoarthritis; Polymorphism, Single Nucleotide; Receptors, Leptin

White adipose tissue (WAT) is a specialized tissue whose main function is lipid synthesis and triglyceride storage. It is now considered as an active organ secreting a plethora of hormones and cytokines namely adipokines. Discovered in 1994, leptin has emerged as a key molecule with pleiotropic functions. It is primarily recognized for its role in regulating energy homeostasis and food intake. Currently, further evidence suggests its potent role in reproduction, glucose metabolism, hematopoiesis, and interaction with the immune system. It is implicated in both innate and adaptive immunity, and it is reported to contribute, with other adipokines, in the cross-talking networks involved in the pathogenesis of chronic inflammation and immune-related diseases of the musculo-skeletal system such as osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the most recent findings concerning the involvement of leptin in immunity and inflammatory responses in OA and RA.

Topics: Adipokines; Arthritis, Rheumatoid; Humans; Immune System Diseases; Inflammation; Leptin; Osteoarthritis

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

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Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.

Topics: Animals; Cartilage, Articular; Humans; Leptin; Osteoarthritis; Receptors, Leptin; Signal Transduction

Metabolic syndrome (MetS) has been associated with osteoarthritis (OA). Leptin, which is one of the markers of MetS, has been associated with OA pathophysiology. This study aimed to provide an update on the association between MetS and OA and on the potential role of leptin in OA. In this review, we summarized the current knowledge of the association between MetS and OA and updated the evidence on the potential role of leptin in OA. Clinical studies have investigated the epidemiologic association between MetS or its components and OA. Results suggested strong epidemiologic associations between MetS and OA, especially in the Asian population. Animal studies also indicated that metabolic dysregulation may lead to OA pathogenesis. The systemic role of MetS in OA pathophysiology is associated with obesity-related inflammation, the beneficial role of n-3 polyunsaturated fatty acids and deleterious role of cholesterol, physical inactivity, hypertension-induced subchondral ischemia, dyslipidemia-induced ectopic lipid deposition in chondrocytes, hyperglycemia-induced local effects of oxidative stress and advanced glycation end-products, low-grade systemic inflammation, and obesity-related adipokines by inducing the expression of proinflammtory factors. Leptin levels in serum/plasma and synovial fluid were associated with joint pain, radiographic progression, bone formation biomarkers, cartilage volume, knee OA incidence, and total joint arthroplasty in OA patients. Elevated leptin expression and increased effect of leptin on infrapatellar fat pad, synovium, articular cartilage, and bone were also involved in the pathogenesis of OA. Current knowledge indicates a convincing epidemiologic association between MetS and OA, especially in the Asian population. Animal studies have also shown that metabolic dysregulation may lead to OA pathogenesis. Accumulating evidence suggests that leptin may play a potential role in OA pathogenesis. Therefore, leptin and its receptor may be an emerging target for intervention in metabolic-associated OA.

Topics: Adipokines; Animals; Chondrocytes; Humans; Inflammation; Leptin; Metabolic Syndrome; Obesity; Osteoarthritis

The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis.. We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments. It is concluded that leptin may lead to OA via some signaling pathways. At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized.. Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person. In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase. Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients.. Treatment for leptin-increased obesity may be a treatment for OA. The role of leptin in OA cannot be ignored and needs to be further studied.

Topics: Arthritis, Rheumatoid; Chondrocytes; Humans; Leptin; Obesity; Osteoarthritis; Risk Factors; Signal Transduction; Synovial Fluid; Weight Loss

Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi-directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune-inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis.

Topics: Adaptive Immunity; Animals; Arthritis, Rheumatoid; Humans; Immune System Diseases; Immunity, Innate; Inflammation; Killer Cells, Natural; Leptin; Neutrophils; Osteoarthritis; Receptors, Leptin

Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.

Topics: Aging; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Basic Helix-Loop-Helix Transcription Factors; Cartilage, Articular; Chondrocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-1beta; Leptin; Nitric Oxide; Osteoarthritis; Tumor Necrosis Factor-alpha

Osteoarthritis (OA) is a complex joint disorder with a number of underlying physical, biochemical, biomechanical and genetic causes. Obesity is considered to be one of the major risk factors for the development and progression of OA. It actively contributes to the inflammatory status and to cartilage degradation in the OA joints. Recent data suggests that metabolic factors produced by white adipose tissue, such as leptin, may provide a mechanistic link between obesity and OA, providing an explanation for the high prevalence of OA among obese and over-weight individuals. The unbalanced production of catabolic and anabolic mediators by chondrocytes, the only cell type present in cartilage, determines cartilage degradation, which is the central pathological feature of OA. Evidence is accumulating to support a key role for leptin in the pathogenesis and/or progression of OA. The goal of this focused review is to summarize the current knowledge on the role of leptin in OA with particular emphasis on the effects of this adipokine in cartilage and chondrocyte pathophysiology.

Topics: Cartilage, Articular; Chondrocytes; Humans; Leptin; Osteoarthritis

Inflammation is a complex mechanism of cell/tissue responses to injuries triggered by multiple causes, including trauma, pathogens or autoimmune abnormal responses. In the last years, a novel line of thought is emerging by giving a more holistic vision of chronic arthropathies through a recently identified group of molecules, called adipokines. Actually, most of these recently identified factors, produced prevalently by white adipose tissue but also by cells of the joints (chondrocytes and synovial fibroblasts) and immune cells, play a significant role in chronic inflammation. Adipokines dysregulation has emerged as a common characteristic of chronic inflammation in rheumatic diseases in particular when obesity or, more precisely, adipose tissue dysfunction is associated with common rheumatic diseases, such as osteoarthritis and rheumatoid arthritis. In this MiniReview, we discuss the role of adipokines in osteoarthritis and rheumatoid arthritis providing an updated overview of their pathophysiological role and potential use as therapeutic targets.

Topics: Adiponectin; Adipose Tissue, White; Animals; Arthritis, Rheumatoid; Humans; Inflammation; Leptin; Osteoarthritis

Osteoarthritis (OA) is the most common cause of musculoskeletal disability and pain in the world. The current drug treatment for OA is symptom relieving, and there is an urgent need for treatments that could retard, prevent or repair cartilage destruction in OA. Obesity is a major risk factor for OA. Traditionally, it has been thought to contribute to the development of OA by increasing the load on weight-bearing joints. However, this appears to be an over-simplification, because obesity is also linked to OA in the hand and finger joints. Recent studies have shown that adipocytokine leptin is a possible link between obesity and OA: Leptin levels in synovial fluid are increased in obese patients, leptin receptor (Ob-R) is expressed in cartilage, and leptin induces the production of matrix metalloproteinases (MMPs), pro-inflammatory mediators and nitric oxide (NO) in chondrocytes. Furthermore, according to the very recent findings, not only leptin levels in the joint but also leptin sensitivity in the cartilage are enhanced in obese OA patients. The findings supporting leptin as a causative link between obesity and OA offer leptin as a potential target to the development of disease-modifying drugs for osteoarthritis (DMOAD), especially for obese patients.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Humans; Leptin; Obesity; Osteoarthritis; Receptors, Leptin; Synovial Fluid

Obesity is currently considered a major public health problem in the world, already reaching epidemic characteristics, according to the World Health Organization. Excess weight is the major risk factor associated with various diseases, such as type 2 diabetes mellitus, hypertension, dyslipidemia and osteometabolic diseases, including osteoporosis and osteoarthritis. Osteoarthritis is the most prevalent rheumatic disease and the leading cause of physical disability and reduced quality of life of the population over 65 years. It mainly involves the joints that bear weight - knees and hips. However, along with the cases of obesity, its prevalence is increasing, and even in other joints, such as hands. Thus, it is assumed that the influence of obesity on the development of OA is beyond mechanical overload. The purpose of this review was to correlate the possible mechanisms underlying the genesis and development of these two diseases. Increased fat mass is directly proportional to excessive consumption of saturated fatty acids, responsible for systemic low-grade inflammation condition and insulin and leptin resistance. At high levels, leptin assumes inflammatory characteristics and acts in the articular cartilage, triggering the inflammatory process and changing homeostasis this tissue with consequent degeneration. We conclude that obesity is a risk factor for osteoarthritis and that physical activity and changes in diet composition can reverse the inflammatory and leptin resistance, reducing progression or preventing the onset of osteoarthritis.

Topics: Cytokines; Humans; Leptin; Obesity; Osteoarthritis; Risk Factors

A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis.

Topics: Adipokines; Adiponectin; Animals; Arthritis, Rheumatoid; Humans; Leptin; Osteoarthritis; Rheumatic Diseases

Osteoarthritis (OA) is a common disease affecting patients at different ages regardless of gender or ethnicity. As with many chronic diseases, OA is thought to have a multifactorial aetiology, which is not fully understood. Whereas the pathophysiological process of OA can be analysed at a cellular and molecular level, the interaction between genes and lifestyle remains an important factor in the development of this disease. The expanding awareness of different genes that may play a role in OA, together with many chemical mediators thought to be associated with the progression of the disease, will help in better management of this condition. Some of the chemical mediators recently implicated in this condition are the adipokines (leptin, adiponectin and resistin). Few but consistent studies suggest that leptin in association with obesity could be an important factor in OA aetiology. Hence, this could establish a strong and direct molecular link between patient life style (nurture) and the pathological process of OA (nature). However, neither a clear mechanism nor a direct clinical association linking leptin to OA has yet been established. In this article, we explore some of the genetic and environmental factors in OA aetiology. We discuss leptin in obesity and assess its possible association with OA aetiology. This should emphasise the important role of health professionals in treating obesity in order to control OA symptoms and possibly progression.

Topics: Disease Progression; Gene-Environment Interaction; Homeostasis; Humans; Leptin; Life Style; Obesity; Osteoarthritis

Osteoarthritis (OA) is a most common multifactorial degenerative joint disease in elderly individuals. OA is affecting severely the quality of life of patients, while the causes of OA are not completely understood. Age, obesity, the female sex, and previous injury are considered as significant risk factors. Recently, increased levels of adipokines which are mainly produced by adipocytes have been detected in patients with osteoarthritis. Moreover, studies on different adipokines all reveal that they have played proinflammatory and catabolic/anabolic roles during the pathophysiology of OA. In the present review, we summarize current data on the effect of the adipose tissue-derived hormones leptin, adiponectin, resistin and visfatin on initiation and progression of OA.

Topics: Adipocytes; Adipokines; Adiponectin; Animals; Disease Progression; Female; Gene Expression Regulation; Humans; Leptin; Male; Mice; Nicotinamide Phosphoribosyltransferase; Osteoarthritis; Resistin; Risk Factors

Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA.

Topics: Adiponectin; Adipose Tissue; Animals; Cytokines; Disease Models, Animal; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Leptin; Obesity; Osteoarthritis; Prevalence; Resistin; Risk Factors; Tumor Necrosis Factor-alpha

Topics: Animals; Humans; Leptin; Metabolic Diseases; Osteoarthritis

Topics: Animals; Cartilage, Articular; Humans; Leptin; Osteoarthritis; Signal Transduction

The present study aimed to assess the prevalence of symptoms of anxiety and depression among health professionals in the three most affected regions in Cameroon.. The study was a descriptive cross-sectional type. Participants were health care professionals working in the three chosen regions of Cameroon. The non_probability convinient sample technique and that of the snowball were valued via a web questionnaire. The non-exhaustive sample size was 292. The diagnosis of anxiety and depression was made by the HAD (Hospital Anxiety and Depression scale).. Les auteurs rapportent que le secteur médical est classé à un plus grand risque de contracter le COVID-19 et de le propager potentiellement à d’autres. Le nombre sans cesse croissant de cas confirmés et suspects, la pression dans les soins, l’épuisement des équipements de protection individuelle et le manque de médicaments spécifiques peuvent contribuer à un vécu anxio-dépressif significatif. La présente étude s’est donnée pour ambition d’évaluer la prévalence des symptômes de l’anxiété et de la dépression chez les professionnels de santé dans les trois Régions les plus concernées au Cameroun.. Le choix des trois Régions du Cameroun se justifie non seulement par le fait qu’elles totalisent 95,8 % des cas de coronavirus au pays depuis le début de la pandémie, mais aussi parce qu’elles disposent de plus de la moitié des personnels de santé (56 %). Il s’agit d’une étude transversale, descriptive et analytique. Les participants sont des professionnels de la santé en service dans les Régions du Centre, Littoral et de l’Ouest du Cameroun. La méthode d’échantillonnage non probabiliste de convenance couplée à celle de boule de neige via un web questionnaire a été adoptée. La collecte des données a duré du 5 au 19 avril 2020, intervalle de temps après lequel on n’avait plus eu de répondants. À la fin de cette période, la taille de l’échantillon non exhaustive était de 292 professionnels. Le diagnostic de l’état anxio-dépressive était posé via l’échelle de HAD (Hospital Anxiety and Depression scale). Dans le HAD, chaque réponse cotée évalue de manière semi-quantitative l’intensité du symptôme au cours de la semaine écoulée. Un score total est obtenu ainsi que des scores aux deux sous-échelles : le score maximal est de 42 pour l’échelle globale et de 21 pour chacune des sous-échelles. Le coefficient alpha de Cronbach est de 0,70 pour la dépression et de 0,74 pour l’anxiété. Certains auteurs après plusieurs travaux ont proposé qu’une note inférieure ou égale à 7 indique une absence d’anxiété ou de dépression ; celle comprise entre 8 et 10 suggère une anxiété ou une dépression faible à bénigne ; entre 11 et 14, pour une anxiété ou une dépression modérée ; enfin, une note comprise entre 15 et 21 est révélatrice d’une anxiété sévère. Le logiciel Excel 2013 et Epi Info version 7.2.2.6 ont été utilisés pour les traitements statistiques. Les liens entre les variables ont été considérées significatifs pour une valeur de. L’amélioration des conditions de travail et notamment la fourniture d’équipement de protection, la mise en place des cellules spéciales d’écoute pour le personnel de santé pourraient être proposées.. Taken together with satisfactory selectivity index (SI) values, the acetone and methanol extracts of. During a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (. In primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.. Beyond age, cognitive impairment was associated with prior MI/stroke, higher hsCRP, statin use, less education, lower eGFR, BMI and LVEF.. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.. Exposure to PM. Respiratory sinus arrhythmia is reduced after PVI in patients with paroxysmal AF. Our findings suggest that this is related to a decrease in cardiac vagal tone. Whether and how this affects the clinical outcome including exercise capacity need to be determined.. BDNF and leptin were not associated with weight. We found that miR-214-5p exerted a protective role in I/R injured cardiac cells by direct targeting FASLG. The results indicated that the MGO injection reduced all CCl. The hepatoprotective effects of MGO might be due to histopathological suppression and inflammation inhibition in the liver.. OVEO showed moderate antifungal activity, whereas its main components carvacrol and thymol have great application potential as natural fungicides or lead compounds for commercial fungicides in preventing and controlling plant diseases caused by. PF trajectories were mainly related to income, pregestational BMI, birth weight, hospitalisation due to respiratory diseases in childhood, participant's BMI, report of wheezing, medical diagnosis and family history of asthma, gestational exposure to tobacco and current smoking status in adolescence and young adult age.. In chronic pain patients on opioids, administration of certain benzodiazepine sedatives induced a mild respiratory depression but paradoxically reduced sleep apnoea risk and severity by increasing the respiratory arousal threshold.. Quantitative measurements of sensory disturbances using the PainVision. The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.. The electrophysiological data and MD simulations collectively suggest a crucial role of the interactions between the HA helix and S4-S5 linker in the apparent Ca. Invited for the cover of this issue are Vanesa Fernández-Moreira, Nils Metzler-Nolte, M. Concepción Gimeno and co-workers at Universidad de Zaragoza and Ruhr-Universität Bochum. The image depicts the reported bimetallic bioconjugates as planes directing the gold fragment towards the target (lysosomes). Read the full text of the article at 10.1002/chem.202002067.. The optimal CRT pacing configuration changes during dobutamine infusion while LV and RV activation timing does not. Further studies investigating the usefulness of automated dynamic changes to CRT pacing configuration according to physiologic condition may be warranted.

Topics: 3' Untranslated Regions; 5'-Nucleotidase; A549 Cells; Accidental Falls; Acetylcholinesterase; Acrylic Resins; Actinobacillus; Acute Disease; Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Adenosine; Adenosine Triphosphate; Administration, Inhalation; Administration, Oral; Adolescent; Adult; Advance Care Planning; Africa, Northern; Age Factors; Aged; Aged, 80 and over; Air Pollutants; Air Pollution; Air Pollution, Indoor; Albendazole; Aluminum Oxide; Anastomosis, Surgical; Ancylostoma; Ancylostomiasis; Androstadienes; Angiogenesis Inhibitors; Angiotensin II; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bispecific; Antibodies, Viral; Anticoagulants; Antihypertensive Agents; Antinematodal Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antiporters; Antiviral Agents; Apoptosis; Aptamers, Nucleotide; Aromatase Inhibitors; Asian People; Astrocytes; Atrial Fibrillation; Auditory Threshold; Aurora Kinase B; Australia; Autophagy; Autophagy-Related Protein 5; Autotrophic Processes; Bacillus cereus; Bacillus thuringiensis; Bacterial Proteins; Beclin-1; Belgium; Benzene; Benzene Derivatives; Benzhydryl Compounds; beta Catenin; beta-Arrestin 2; Biliary Tract Diseases; Biofilms; Biofuels; Biomarkers; Biomarkers, Tumor; Biomass; Biomechanical Phenomena; Bioreactors; Biosensing Techniques; Biosynthetic Pathways; Bismuth; Blood Platelets; Bone and Bones; Bone Regeneration; Bortezomib; Botulinum Toxins, Type A; Brain; Brain Injuries; Brain Ischemia; Brain Neoplasms; Breast Neoplasms; Breath Tests; Bronchodilator Agents; Calcium Phosphates; Cannabis; Carbon Dioxide; Carbon Isotopes; Carcinogenesis; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Cardiomyopathies; Cardiovascular Diseases; Cariostatic Agents; Case Managers; Case-Control Studies; Catalysis; Cation Transport Proteins; CD8-Positive T-Lymphocytes; Cecropia Plant; Cell Adhesion; Cell Count; Cell Differentiation; Cell Division; Cell Line; Cell Line, Tumor; Cell Membrane; Cell Movement; Cell Proliferation; Cell Self Renewal; Cell Survival; Cells, Cultured; Cellular Reprogramming; Cellulose; Charcoal; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemokines; Chemoradiotherapy; Chemoreceptor Cells; Child; Child Abuse; Child, Preschool; China; Chlorogenic Acid; Chloroquine; Chromatography, Gas; Chronic Disease; Clinical Competence; Coated Materials, Biocompatible; Cochlea; Cohort Studies; Color; Comorbidity; Computer Simulation; Computer-Aided Design; Contraception; Contraceptive Agents, Female; Contrast Media; COP-Coated Vesicles; Coronavirus Infections; Cost of Illness; Coturnix; COVID-19; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Culex; Curriculum; Cyclic N-Oxides; Cytokines; Cytoplasm; Cytotoxicity, Immunologic; Cytotoxins; Databases, Factual; Deep Learning; Delivery, Obstetric; Denitrification; Dental Caries; Denture, Complete; Dexamethasone; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dielectric Spectroscopy; Diet, High-Fat; Dietary Fiber; Disease Models, Animal; Disease Progression; DNA; DNA Copy Number Variations; DNA, Mitochondrial; Dog Diseases; Dogs; Dopaminergic Neurons; Double-Blind Method; Down-Regulation; Doxorubicin; Drug Carriers; Drug Design; Drug Interactions; Drug Resistance, Bacterial; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Drugs, Chinese Herbal; Dry Powder Inhalers; Dust; E2F1 Transcription Factor; Ecosystem; Education, Nursing; Education, Nursing, Baccalaureate; Electric Impedance; Electricity; Electrocardiography; Electrochemical Techniques; Electrochemistry; Electrodes; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum; Endothelial Cells; Environmental Monitoring; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; 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Mitochondrial Proteins; Mitral Valve; Mitral Valve Insufficiency; Models, Anatomic; Molecular Structure; Molybdenum; Monocarboxylic Acid Transporters; Moths; MPTP Poisoning; Multigene Family; Multiparametric Magnetic Resonance Imaging; Multiple Myeloma; Muscle, Skeletal; Mutagens; Mutation; Myeloid Cells; Nanocomposites; Nanofibers; Nanomedicine; Nanoparticles; Nanowires; Neoadjuvant Therapy; Neomycin; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasms; Neoplastic Stem Cells; Neostriatum; Neovascularization, Pathologic; Netherlands; Neuromuscular Agents; Neurons; NF-E2-Related Factor 2; NF-kappa B; Nickel; Nitrogen Oxides; Non-alcoholic Fatty Liver Disease; Nucleosides; Nucleotidyltransferases; Nutritional Status; Obesity, Morbid; Ofloxacin; Oils, Volatile; Oligopeptides; Oncogene Protein v-akt; Optical Imaging; Organic Cation Transport Proteins; Organophosphonates; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteogenesis; Oxidation-Reduction; Oxidative Stress; 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Skull Fractures; Social Determinants of Health; Sodium; Sodium Fluoride; Sodium Potassium Chloride Symporter Inhibitors; Sodium-Glucose Transporter 2 Inhibitors; Soil; Soil Pollutants; Spain; Spectrophotometry; Spectroscopy, Fourier Transform Infrared; Staphylococcal Protein A; Staphylococcus aureus; Stem Cells; Stereoisomerism; Stomach Neoplasms; Streptomyces; Strontium; Structure-Activity Relationship; Students, Nursing; Substance-Related Disorders; Succinic Acid; Sulfur; Surface Properties; Survival Rate; Survivin; Symporters; T-Lymphocytes; Temozolomide; Tensile Strength; Thiazoles; Thiobacillus; Thiohydantoins; Thiourea; Thrombectomy; Time Factors; Titanium; Tobacco Mosaic Virus; Tobacco Use Disorder; Toll-Like Receptor 4; Toluene; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Toxicity Tests, Acute; Toxicity Tests, Subacute; Transcriptional Activation; Treatment Outcome; Troponin I; Tumor Cells, Cultured; Tumor Escape; Tumor Hypoxia; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Tyrosine; Ubiquitin-Protein Ligases; Ubiquitination; Ultrasonic Waves; United Kingdom; United States; United States Department of Veterans Affairs; Up-Regulation; Urea; Uric Acid; Urinary Bladder Neoplasms; Urinary Bladder, Neurogenic; Urine; Urodynamics; User-Computer Interface; Vemurafenib; Verbenaceae; Veterans; Veterans Health; Viral Load; Virtual Reality; Vitiligo; Water Pollutants, Chemical; Wildfires; Wnt Signaling Pathway; Wound Healing; X-Ray Diffraction; Xenograft Model Antitumor Assays; Xylenes; Young Adult; Zinc; Zinc Oxide; Zinc Sulfate; Zoonoses

The present study explores the possible connection between synovial fluid concentrations of insulin like growth factor (IGF-1), IGF-binding protein (IGFBP-3), leptin, and C-reactive protein (CRP) in osteoarthritis (OA). Synovial fluid specimens were obtained from a total of thirty-four individuals with and without OA. Protein-normalized measurements of IGF-1, IGFBP-3, and leptin concentrations in synovial fluid showed significantly (P < 0.05) elevated levels in women with knee OA but not in men. This study provides initial evidence that protein normalized IGF-1 and IGFBP-3 and leptin levels increase in synovial fluid of women but not in men with OA versus those without OA.

Topics: Adult; Aged; C-Reactive Protein; Female; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Leptin; Male; Middle Aged; Osteoarthritis; Sex Characteristics; Synovial Fluid

To investigate the therapeutic effect and mechanism of metformin on knee OA in normal diet (ND) mice or high-fat diet (HFD)-induced obese mice.. Destabilization of the medial meniscus surgery was performed in ND mice or HFD mice, and metformin was administrated in drinking water or not. The changes of OA joint structure, infiltration and polarization of synovial macrophages and circulating and local levels of leptin and adiponectin were evaluated. In vitro, the effects of metformin on chondrocytes and macrophages, and of conditioned mediums derived from mouse abdominal fat on murine chondrogenic cell line ATDC5 and murine macrophage cell line RAW264.7, were detected.. Metformin showed protective effects on OA, characterized by reductions on OARSI score [2.00, 95% CI (1.15, 2.86) for ND mice and 3.17, 95% CI (2.37, 3.96) for HFD mice] and synovitis score [1.17, 95% CI (0.27, 2.06) for ND mice and 2.50, 95% CI (1.49, 3.51) for HFD mice] after 10 weeks of treatment, and the effects were more significant in HFD mice than in ND mice. Mechanistically, in addition to decreasing apoptosis and matrix-degrading enzymes expression in chondrocytes as well as infiltration and pro-inflammatory differentiation of synovial macrophages, metformin reduced leptin secretion by adipose tissue in HFD mice.. Metformin protects against knee OA which could be through reducing apoptosis and catabolism of chondrocytes, and suppressing infiltration and pro-inflammatory polarization of synovial macrophages. For obese mice, metformin has a greater protective effect in knee OA additionally through reducing leptin secretion from adipose tissue.

Topics: Adipocytes; Animals; Chondrocytes; Diet, High-Fat; Leptin; Macrophages; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; Osteoarthritis

Topics: Adipose Tissue; Humans; Leptin; Obesity; Osteoarthritis

Topics: Cartilage, Articular; Cells, Cultured; Chondrocytes; Female; Humans; Leptin; Metabolic Syndrome; Osteoarthritis; Phenotype

The pathophysiology of osteoarthritis (OA) is closely linked to autophagy abnormalities in articular chondrocytes, the sole mature cell type in healthy cartilage. Nevertheless, the precise molecular mechanism remains uncertain. Previous research has demonstrated that leptin activates mTORC1 , thereby inhibiting chondrocyte autophagy during the progression of OA. In this study, it is demonstrated that the presence of leptin induces a substantial increase in the expression of STAT3, leading to a notable decrease in REDD1 expression and subsequent phosphorylation of p70S6K, a recognized downstream effector of mTORC1. Conversely, inhibition of leptin yields contrasting effects. Additionally, the potential advantages of utilizing a sustained intra-articular release of a leptin inhibitor (LI) via an injectable, thermosensitive poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PDLLA-PEG-PDLLA: PLEL) hydrogel delivery system for the purpose of investigating its impact on cartilage repair are explored. The study conducted on LI-loaded PLEL (PLEL@LI) demonstrates remarkable efficacy in inhibiting OA and displays encouraging therapeutic advantages in the restoration of subchondral bone and cartilage. These findings establish a solid foundation for the advancement of a pioneering treatment approach utilizing PLEL@LI for OA.

Topics: Autophagy; Cartilage, Articular; Chondrocytes; Delayed-Action Preparations; Humans; Hydrogels; Leptin; Mechanistic Target of Rapamycin Complex 1; Osteoarthritis; Regeneration; STAT3 Transcription Factor

Osteoarthritis is one of the usual chronic musculoskeletal dysfunctions. It is one of the primary leading causes which leads to limitation of movement and absenteeism in the working adult population. Chondrocytes are the singlecellular-based component found in the cartilage which has an important role in the degradation of the cartilage. In recent studies, autophagy is observed to protect the human chondrocytes from stress.Leptin an adipokine managing food consumption and energy outlay. Chondrocytes indicate prolonged isoform of the leptin receptor where inside these cells theleptin signals individually or combine with the remaining molecules and promptthe indication of the pro-inflammatory molecules and cartilage disintegration enzymes.. mRNA expressions of Lysyl oxidase-like 3 in tissues of cartilage and concentration of leptin from synovial fluidwere measured from all samples from disease-induced groups, sham group, and RAPA-treated groups via RT-PCR and immunoassays. Histopathological analysis was also performed post-induction of the rat osteoarthritis model by the anterior cruciate ligament transection method. Western blot analysis was done, and expressions were analyzed by autophagy and apoptosis regulatory markers. Cell apoptosis and cell survival were evaluated with the help of flow cytometry, respectively, in all groups.. mRNA of LOXL3 was increased in osteoarthritis models which were directly related to leptin concentration in SF. ACLT surgery caused an increase in cleaved caspase 3 protein levels, while a significant reduction in Bcl-2, Beclin1, and LC3 I was noted (figure 4,5). When LOXL3 was silenced in the ACLT group and leptin-treated group apoptosis was inhibited and autophagy, cell proliferation was promoted in primary chondrocytes. A significant increase in LOXL3 caused inhibition of autophagy in chondrocytes.. LOXL3 has stimulated apoptosis while inhibited autophagy in chondrocytes; hence LOXL3 is a prominent target for treating osteoarthritis. Keywords:chondrocytes, LOXL3, Leptin, osteoarthritis, qRT-PCR, ACLT, mRNA.

Topics: Amino Acid Oxidoreductases; Animals; Apoptosis; Autophagy; Chondrocytes; Humans; Leptin; Osteoarthritis; Rats; RNA, Messenger; Up-Regulation

Leptin and ROS are implicated in the regulation of inflammatory pathways including NLRP3-inflammasome. We investigated the functional link between leptin, ROS and NLRP3-inflammasome formation/activation in osteoarthritis (OA), an age-related disease. We found that inflammasome components' (NLRP3, ASC, Caspase-1 and cleaved Caspase-1) protein expression were increased in OA cartilage biopsies and chondrocytes compared to healthy cartilage and chondrocytes. Immunofluorescence showed increased co-localization of NLRP3/ASC and NLRP3/Caspase-1, ASC-specks formation and ROS levels in OA compared to normal chondrocytes. NOX4 mRNA expression and IL-1β/IL-18 secretion levels were also elevated in OA chondrocytes. Furthermore, NLRP3-siRNA in OA chondrocytes revealed significant MMP-9/MMP-13 downregulation. To elucidate leptin/ROS/NLRP3-inflammasome interactions, OA chondrocytes were treated with ROS-inhibitor NAC, NOXs-inhibitor DPI, NOX4-inhibitor GLX351322 and leptin-siRNA, while normal chondrocytes were incubated with leptin with or without DPI or GLX351322. We observed attenuated ROS levels and NLRP3-inflammasome formation/activation in NAC-, DPI- or GLX351322-treated OA chondrocytes, while the same effect was shown after transfection with leptin-siRNA. Furthermore, incubation of normal chondrocytes with leptin enhanced ROS production and inflammasome formation/activation, while pretreatment with DPI or GLX351322 abolished leptin's stimulatory effects confirming leptin-NOX4-ROS-inflammasome regulatory axis. Overall, our findings provide novel evidence indicating that leptin-induced NLRP3-inflammasome formation/activation in OA chondrocytes is mediated by NOX4-dependent ROS production.

Topics: Caspase 1; Chondrocytes; Humans; Inflammasomes; Interleukin-1beta; Leptin; NLR Family, Pyrin Domain-Containing 3 Protein; Osteoarthritis; Reactive Oxygen Species; RNA, Small Interfering

To explore how systemic factors that modify knee osteoarthritis risk are connected to 'whole-joint' structural changes by evaluating the effects of high-fat diet and wheel running exercise on synovial fluid (SF) metabolomics.. Male mice were fed a defined control or high-fat (60% kcal fat) diet from 6 to 52 weeks of age, and half the animals were housed with running wheels from 26 to 52 weeks of age (n = 9-13 per group). Joint tissue structure and osteoarthritis pathology were evaluated by histology and micro-computed tomography. Systemic metabolic and inflammatory changes were evaluated by body composition, glucose tolerance testing, and serum biomarkers. SF metabolites were analyzed by high performance-liquid chromatography mass spectrometry. We built correlation-based network models to evaluate the connectivity between systemic and local metabolic biomarkers and osteoarthritis structural pathology within each experimental group.. High-fat diet caused moderate osteoarthritis, including cartilage pathology, synovitis and increased subchondral bone density. In contrast, voluntary exercise had a negligible effect on these joint structure components. 1,412 SF metabolite features were detected, with high-fat sedentary mice being the most distinct. Diet and activity uniquely altered SF metabolites attributed to amino acids, lipids, and steroids. Notably, high-fat diet increased network connections to systemic biomarkers such as interleukin-1β and glucose intolerance. In contrast, exercise increased local joint-level network connections, especially among subchondral bone features and SF metabolites.. Network mapping showed that obesity strengthened SF metabolite links to blood glucose and inflammation, whereas exercise strengthened SF metabolite links to subchondral bone structure.

Topics: Animals; Biomarkers; Chemokine CCL2; Chondrocytes; Diet, High-Fat; Glucose Intolerance; Hypertrophy; Interleukin-10; Interleukin-1beta; Interleukin-8; Leptin; Metabolomics; Mice, Inbred C57BL; Osteoarthritis; Physical Conditioning, Animal; Stifle; Synovial Fluid; X-Ray Microtomography

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage's integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Topics: Adiponectin; Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Biomarkers; Cartilage, Articular; Cholecalciferol; Collagen Type II; Disease Models, Animal; Leptin; Matrix Metalloproteinase 3; Meniscectomy; Menisci, Tibial; Osteoarthritis; Peptide Fragments; Rats; Rats, Wistar; Tibia

Obesity is considered as a risk factor of osteoarthritis (OA), but the precise relationship is still poorly understood. Leptin, one of the most relevant factors secreted by adipose tissues, plays an important role in the pathogenesis of OA. Our aim was to investigate the regulation and molecular mechanism of the leptin signaling pathway in obesity-related OA. SD rats were fed with a high-fat diet (HFD) for 5, 15, and 27 weeks. The levels of leptin in serum increased from W5, while in the synovial fluid increased from W15. The histological evaluation showed that the pathological changes of OA occurred at 27 weeks rather than 5 or 15 weeks. We also found that leptin induced CD14/TLR4 activation by the JAK2-STAT3 signaling pathway to promote OA. Moreover, silencing SOCS3 enhanced leptin-induced JAK2-STAT3-CD14/TLR4 activation in rat primary chondrocytes. Our findings indicated that leptin may be one of the initiating factors of obesity-related OA. TLR4 is at least partially regulated by leptin through the JAK2-STAT3-CD14 pathway. Meanwhile, SOCS3 acting as a negative feedback inhibitor of leptin signaling presented a potential therapeutic prospect for obesity-related OA. Our study provided new evidence suggesting the key role of leptin in mediating obesity-related OA process and its underlying mechanisms.

Topics: Animals; Gene Expression Regulation; Janus Kinase 2; Leptin; Male; Obesity; Osteoarthritis; Rats; Rats, Sprague-Dawley; STAT3 Transcription Factor; Toll-Like Receptor 4

Resveratrol (RES) has a protective effect on osteoarthritis (OA), nevertheless, the underlying mechanisms of RES towards obesity-related OA are still unclear. This study is aimed to determine whether leptin resistant mechanism presents in articular cartilage of obesity-related OA and whether the protective effect of RES is involved in the regulation of leptin signal by affecting suppressor of cytokine signaling 3 (SOCS3). Male C57BL/6 J mice were fed with standard chow diet, high fat diet (HFD) or high fat diet with RES (45 mg/kg.bw) for 22 weeks. Knee joints of mice were evaluated by histological and immunohistochemistry analysis. Serum level of leptin was measured by ELISA. The leptin, leptin receptor (OB-Rb), SOCS3 mRNA expression and JAK2, STAT3, OB-Rb and SOCS3 protein expression in cartilage were determined by real-time RT-PCR and western blot. In addition, SW1353 cells were pretreated with or without AG490, and stimulated with leptin in the presence or absence of RES to detect JAK2, STAT3, matrix metalloproteinase-13 (MMP-13) and SOCS3 expression. We found that HFD could induce obesity-related OA and RES prevented its progression. Serum leptin and mRNA expression in cartilage was up-regulated by HFD, while RES ameliorated the elevation. Besides, RES significantly inhibited the JAK2/STAT3 signaling pathway in cartilage, as well as SOCS3. In in vitro study, RES exhibited the same effect in SW1353 cells which stimulated with leptin. In conclusion, no significant leptin resistance existed in cartilage of obesity-related OA and the inhibitory effect of RES on obesity-related OA via alleviating JAK2/STAT3 signaling pathway is independent of SOCS3.

Topics: Animals; Cell Line, Tumor; Diet, High-Fat; Disease Models, Animal; Disease Progression; Humans; Janus Kinase 2; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis; Resveratrol; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased

Topics: Aged; Animals; Body Mass Index; Bone Marrow; Cell Culture Techniques; Chondrocytes; Chondrogenesis; Collagen Type II; Estradiol; Extracellular Matrix; Female; Humans; Immunohistochemistry; Interleukin-1beta; Interleukin-6; Leptin; Male; Middle Aged; Multivariate Analysis; Osteoarthritis; Oxytocin; Rats; RNA, Messenger; SOX9 Transcription Factor; Stem Cells

Joint damage in patients with diabetes mellitus (DM) is a common complication and is associated with the induction of metabolic inflammation against the background of increased catabolic processes in various joint structures. The aim of our work was to study the level of insulin, leptin, osteocalcin, as well as biochemical markers of connective tissue metabolism in patients with diabetes-associated osteoarthritis. We examined 77 patients who were divided into groups by type of diabetes, the presence and severity of diabetic arthropathy. The content of insulin and leptin, osteocalcin in the blood serum was determined by the enzyme immunoassay, the level of glycosaminoglycans, hydroxyproline, hyaluronidase, collagenase according to traditional biochemical methods. Among the examined patients, diabetic arthropathy was diagnosed in more than 70%. Patients with diabetic arthropathy significantly increased levels of insulin (with type 1 diabetes by 38.5%, with type 2 diabetes by 55.6%) and leptin (with type 1 diabetes by 43.8%, with type 2 diabetes by 53.7,%), the level of osteocalcin (only with type 1 diabetes by 53.9%) There is a direct correlation between the severity of joint damage and the level of insulin and leptin. The severity of arthopathy in patients with type 2 diabetes is directly correlated with indicators of insulin resistance. In patients with diabetes-associated osteoarthritis, indicators that characterize catabolic processes in the connective tissue (hydroxyproline free and collagenase (p<0.001) are increased. The chances of detecting arthropathy with type 1 diabetes increase 3.8 times with an increase in insulin levels, with an increase in leptin 1.3 times, in patients with type 2 diabetes, 2.6 and 1.2 times, respectively. For this sample, it was found that the development of arthropathy does not depend on the type of diabetes. In women with type 2 diabetes, the chances of developing arthropathy are six times higher. 4 times than men. An increase in insulin and leptin levels can serve as a marker for the presence and progression of arthropathy in patients with diabetes. Patients with arthropathies have increased levels of hydroxyproline and collagenase, which reflects an increase in catabolic processes in the connective tissue, which may be one of the mechanisms for the development of joint structures in patients with diabetes.

Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Osteoarthritis

With increasing evidence regarding the metabolic basis of osteoarthritis (OA), we studied the relationship between adipose tissue and OA.. This study is part of an OA registry in the eastern part of Fars Province, Iran. Overall, 150 patients with OA and 300 sex matched individuals were selected as a control group. They were compared regarding adipokine concentration (leptin, adiponectin, resistin and visfatin), anthropo-metric indices, the Western Ontario and McMaster universities arthritis index score (WOMAC).. All adipokine levels were higher among OA patients (p<0.001). After adjusting for age, sex, and body mass index (BMI), adipokines showed a significant and positive association with OA (B: 14.12, B: 9.92, B: 24.71 and B: 12.29 for leptin, adiponectin, visfatin, and resistin, respectively; p<0.001). Except the adiponectin that had a negative relationship with BMI in the OA group (r=-0.570, p<0.001), other adipokines had positive relationships with BMI (r=0.781, p<0.001; r=0.530, p<0.001; r=0.549, p<0.001 for leptin, visfatin, and resistin, respectively). Only leptin and adiponectin levels were correlated with pain (B: 0.045, -0.079 and p<0.05).. The present study shows that aside to the well-known role of mechanical stress in OA pathogenesis (weight load), leptin, adiponectin, visfatin, and resistin, which represent the adi-pose tissue independent on the weight, may play a chemical role in OA pathogenesis. In addition, leptin and adiponectin may be involved in the pain levels among patients with OA.

Topics: Adiponectin; Adipose Tissue; Adult; Aged; Arthralgia; Body Mass Index; Cytokines; Female; Humans; Iran; Leptin; Male; Middle Aged; Nicotinamide Phosphoribosyltransferase; Osteoarthritis; Registries; Resistin

Cartilage repair in osteoarthritic patients remains a challenge. Identifying resident or donor stem/progenitor cell populations is crucial for augmenting the low intrinsic repair potential of hyaline cartilage. Furthermore, mediating the interaction between these cells and the local immunogenic environment is thought to be critical for long term repair and regeneration. In this study we propose articular cartilage progenitor/stem cells (CPSC) as a valid alternative to bone marrow-derived mesenchymal stem cells (BMMSC) for cartilage repair strategies after trauma. Similar to BMMSC, CPSC isolated from osteoarthritic patients express stem cell markers and have chondrogenic, osteogenic, and adipogenic differentiation ability. In an in vitro 2D setting, CPSC show higher expression of SPP1 and LEP, markers of osteogenic and adipogenic differentiation, respectively. CPSC also display a higher commitment toward chondrogenesis as demonstrated by a higher expression of ACAN. BMMSC and CPSC were cultured in vitro using a previously established collagen-chondroitin sulfate 3D scaffold. The scaffold mimics the cartilage niche, allowing both cell populations to maintain their stem cell features and improve their immunosuppressive potential, demonstrated by the inhibition of activated PBMC proliferation in a co-culture setting. As a result, this study suggests articular cartilage derived-CPSC can be used as a novel tool for cellular and acellular regenerative medicine approaches for osteoarthritis (OA). In addition, the benefit of utilizing a biomimetic acellular scaffold as an advanced 3D culture system to more accurately mimic the physiological environment is demonstrated.

Topics: Aggrecans; Cartilage, Articular; Cell Culture Techniques; Cells, Cultured; Chondrogenesis; Gene Expression; Gene Expression Regulation, Developmental; Humans; Leptin; Osteoarthritis; Osteopontin; Stem Cells; Tissue Scaffolds

The current study aims to investigate the diagnostic value of serum proinflammatory factors, including IL-6, TNF-α, and leptin, in patients with post-traumatic osteoarthritis (PTOA).. The serum levels of IL-6, TNF-α, and leptin were detected by enzyme linked immunosorbent assay (ELISA). Pearson's correlation assay was performed to evaluate the correlation between serum levels of IL-6, TNF-α, and leptin. ROC analysis was carried out to explore the diagnostic value of IL-6, TNF-α, and leptin for PTOA patients.. Compared with the control group, the levels of IL-6, TNF-α, and leptin in the serum of patients with PTOA were significantly higher. Moreover, the levels of IL-6, TNF-α, and leptin increased along with Kellgren Lawrence (K-L) grading in patients with PTOA. Pearson's correlation analysis showed that serum IL-6 was positively correlated with TNF-α and leptin, and TNF-α was positively correlated with leptin. More importantly, the AUC of combined serum IL-6, TNF-α, and leptin levels in PTOA patients was 0.946 with the sensitivity and specificity of 97% and 61%, which was close to the AUC of X-ray results (0.972, with the sensitivity and specificity 63% and 96%).. In summary, combined use of serum TNF-α, IL-6, and leptin levels can act as biomarkers to distinguish between PTOA patients and healthy controls before standard radiography.

Topics: Biomarkers; Humans; Interleukin-6; Leptin; Osteoarthritis; Tumor Necrosis Factor-alpha

To investigate associations of leptin and adiponectin levels with knee and hand osteoarthritis, and explore whether these mediate the association between adiposity and osteoarthritis.. This is a cross-sectional analysis of baseline data from the population-based Netherlands Epidemiology of Obesity study. Adiposity was assessed with body mass index (BMI) and percentage total body fat (%TBF). Osteoarthritis, defined as hand or knee osteoarthritis, was determined using American College of Rheumatology criteria. Fasting serum adipokine levels were measured using immunoassays. Associations between adiposity and osteoarthritis were examined with logistic regression, adjusted for age, sex, ethnicity and education, and additionally for leptin and adiponectin as potential mediators.. In 6408 participants (56% women, median age 56 years), prevalence of osteoarthritis was 22% (10% isolated knee and 8% isolated hand osteoarthritis). Leptin levels were positively associated with osteoarthritis, while adiponectin levels were not. Leptin partially mediated the association of adiposity with osteoarthritis (OR 1.40 (95%CI 1.30; 1.52) attenuated to 1.38 (1.24; 1.54) per 5 units BMI and OR 1.25 (1.17; 1.35) to 1.20 (1.10; 1.32) per 5 units %TBF, representing 4% and 17% mediation, respectively). Larger proportion mediation by leptin was found in knee (13%/27%) than in hand osteoarthritis (9%/18%). Sex-stratified analyses generally showed stronger associations between adiposity, leptin and osteoarthritis in women than in men.. Serum leptin levels were associated with osteoarthritis, and partially mediated the association between adiposity and osteoarthritis, while adiponectin levels were not associated with osteoarthritis. These findings provide evidence for systemic effects of adipose tissue in osteoarthritis.

Topics: Adiponectin; Adiposity; Aged; Female; Hand Joints; Humans; Leptin; Logistic Models; Male; Middle Aged; Netherlands; Obesity; Osteoarthritis; Osteoarthritis, Knee

Authors discuss the musculoskeletal aspects of obesity by applying a novel approach. Biochemical changes associated with obesity and especially metabolic syndrome, may have a great impact on the function of bones, joints and muscles. Therefore we need a new view and new strategies in rheumatic diseases. Obesity-associated metabolic changes should be considered during the progress of as well as the selection of treatment in inflammatory rheumatic diseases. Individualised treatment is necessary due to associated comorbidities as well. Orv Hetil. 2019; 160(44): 1727-1734.. Absztrakt: A szerzők az elhízás mozgásszervi vonatkozásait új megközelítésben, elsősorban annak metabolikus hatásait kiemelve ismertetik. Az elhízással és különösen a metabolikus szindrómával járó biokémiai változások megváltoztatják a csont, az ízületi struktúrák és az izomzat működését. Ezek alapján szemléletváltozás szükséges bizonyos kórképekben az eddig kialakult nézetekben. A gyulladásos reumatológiai betegségek lefolyásának súlyosságában és az alkalmazott kezelések megválasztásában is figyelembe kell venni az elhízással járó anyagcsere-változásokat. A társuló komorbiditások miatt a személyre szabott kezelés fontossága kiemelt jelentőségű. Orv Hetil. 2019; 160(44): 1727–1734.

Topics: Adipokines; Arthritis; Humans; Joint Diseases; Leptin; Metabolic Syndrome; Musculoskeletal Diseases; Obesity; Osteoarthritis; Rheumatic Diseases

Topics: Adult; Aged; Asian People; Body Mass Index; DNA Methylation; Female; Humans; Leptin; Male; Middle Aged; Obesity; Osteoarthritis; Promoter Regions, Genetic; Taiwan

This study was conducted to measure concentrations of leptin and interleukin-6 (IL-6) in the synovial fluid (SF) of 38 patients with temporomandibular disorders (TMDs) and 7 healthy controls and to analyze the correlation between leptin and IL-6.. Patients with TMDs were divided into 3 subgroups according to imaging and clinical findings: displaced disc with reduction (DDR; n = 12), displaced disc without reduction (DDNR; n = 13), and osteoarthritis (OA; n = 13). SF samples were collected, and leptin and IL-6 levels were measured by enzyme-linked immunosorbent assay.. No relevant difference in leptin level was found between the control group and the DDR or DDNR group, whereas the OA group presented a higher leptin concentration than all other groups. IL-6 concentrations were markedly higher in all patient groups than in the control group. Levels were markedly higher in the OA group than in the DDR or DDNR group, but no relevant differences were found between the DDR and DDNR groups. No relevant correlation was found between leptin and IL-6 concentrations.. Distinct changes in leptin and IL-6 concentrations in the SF occurred at different stages of TMDs, suggesting their potential role in the pathogenesis of TMDs.

Topics: Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-6; Leptin; Osteoarthritis; Synovial Fluid; Temporomandibular Joint Disorders

Leptin, through binding to its special receptor (Ob-Rb), has potent effects on immunity and inflammation. This study measured the levels of leptin in the synovial fluid of patients with temporomandibular joint osteoarthritis (TMJ-OA) and healthy controls, determined the expression of Ob-Rb and explored the effects and signalling pathways involved in leptin-induced proinflammatory cytokine interleukin (IL)-6 production in TMJ synovial fibroblasts (TMJ-SFs).. Synovial fluid samples were obtained from 16 patients with TMJ-OA and seven healthy controls. Leptin levels were measured in synovial fluid using enzyme-linked immunosorbent assay (ELISA). Ob-Rb expression was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot in cultured TMJ-SFs. Small interfering RNA (siRNA) was transfected into the TMJ-SFs to down-regulate the expression of Ob-Rb. qRT-PCR and ELISA were used to determine the levels of proinflammatory cytokine IL-6 in leptin-stimulated TMJ-SFs. The involved signalling pathways that mediate the leptin-stimulated production of IL-6 were investigated using specific signalling inhibitor analyses.. Compared with healthy controls, patients with TMJ-OA had significantly higher concentrations of leptin in their synovial fluid. The expression levels of Ob-Rb mRNA and proteins were detected in the TMJ-SFs. Leptin can stimulate the mRNA and protein expression of IL-6 in TMJ-SFs by binding with Ob-Rb. The leptin-induced production of IL-6 by the TMJ-SFs significantly decreased after exposure to siRNA targeting Ob-Rb. Inhibiting JAK2/STAT3, p38 MAPK or PI3K/Akt substantially decreased leptin-induced IL-6 production.. Leptin may up-regulate IL-6 production in vitro by binding with Ob-Rb in TMJ-SFs via the activation of the JAK2/STAT3, p38 MAPK or PI3K/Akt signalling pathways.

Topics: Adult; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Gene Expression; Humans; Inflammation Mediators; Interleukin-6; Janus Kinase 2; Leptin; Male; MAP Kinase Signaling System; Osteoarthritis; Phosphatidylinositol 3-Kinases; Real-Time Polymerase Chain Reaction; Receptors, Leptin; RNA, Messenger; RNA, Small Interfering; Synovial Fluid; Synovial Membrane; Temporomandibular Joint; Young Adult

To evaluate the relationship between serum and synovial fluid (SF) leptin concentrations and body condition score (BCS) in healthy and osteoarthritic dogs.. Controlled, prospective, clinical study.. Nineteen healthy dogs and 29 dogs with osteoarthritis (OA) secondary to cranial cruciate ligament injury.. Synovial fluid was obtained from the femorotibial joint under sedation (healthy dogs) or during surgery (OA dogs). Serum and SF leptin and interleukin (IL)-1β concentrations were measured via enzyme-linked immunosorbent assay. Dogs were classified as optimal weight (BCS 4-5/9) or overweight (BCS >5/9). Radiographs were scored for OA severity by a radiologist. Owners completed the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire.. Mean (± SD) SF leptin (4.09 ± 4 ng/mL) was lower than serum leptin (6.88 ± 5.52 ng/mL, P < .0001). Synovial fluid leptin was higher in overweight (5.28 ± 4.21) than in optimal body weight dogs (1.54 ± 1.72 ng/mL, P < .0001). Serum (P < .001) and SF leptin (P = .004) concentrations were associated with BCS. Concentration of SF leptin did not differ between healthy (2.4 ± 2.04 ng/mL) and OA (4.9 ± 4.3 ng/mL, P = .25) dogs. Synovial fluid leptin and LOAD scores were weakly associated (P = .03). No association was detected between SF leptin and radiographic score or IL-1β (P = .73).. Serum and SF leptin correlated with BCS in this population. Synovial fluid leptin was weakly associated with LOAD scores but not with radiographic severity of OA or IL-1β.. Serum and SF leptin concentrations do not predict radiographic severity of canine OA but contribute to joint pain and dysfunction.

Topics: Animals; Anterior Cruciate Ligament Injuries; Body Composition; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Humans; Leptin; Male; Osteoarthritis; Prospective Studies; Radiography; Synovial Fluid

Particles generated from wear of prosthesis joint bearing surfaces induce inflammation-mediated periprosthetic bone resorption (osteolysis). Morbidly obese leptin-deficient ob/ob mice are resistant to polyethylene particle-induced bone loss, suggesting that leptin, a hormone produced by adipocytes that circulates in concentrations proportional to total body adiposity, increases osteolysis. To confirm that particles induce less osteolysis in leptin-deficient mice after controlling for cold stress (room temperature)-induced bone loss, ob/ob mice on a C57BL/6 (B6) background and colony B6 wildtype (WT) mice housed at thermoneutral temperature were randomized to control or particle treatment groups (N = 5/group). Polyethylene particles were implanted over calvaria and mice sacrificed 2 weeks later. Compared to particle-treated WT mice, particle-treated ob/ob mice had lower osteolysis score, less infiltration of immune cells, and less woven bone formation. To determine the role of leptin in particle-induced osteolysis, ob/ob mice were randomized into one of 4 groups (n = 6-8/group): (1) control, (2) particles, (3) particles + continuous leptin (osmotic pump, 6 μg/d), or (4) particles + intermittent leptin (daily injection, 40 μg/d). Leptin treatment increased particle-induced osteolysis in ob/ob mice, providing evidence that the adpiokine may play a role in inflammation-driven bone loss. Additional research is required to determine whether altering leptin levels within the physiological range results in corresponding changes in polyethylene-particle-induced osteolysis.

Topics: Animals; Female; Leptin; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Osteoarthritis; Osteolysis; Prostheses and Implants

Increasing evidence suggests that inflammation plays a central role in driving joint pathology in certain patients with osteoarthritis (OA). Since many patients with OA are obese and increased adiposity is associated with chronic inflammation, we investigated whether obese patients with hip OA exhibited differential pro-inflammatory cytokine signalling and peripheral and local lymphocyte populations, compared to normal weight hip OA patients. No differences in either peripheral blood or local lymphocyte populations were found between obese and normal-weight hip OA patients. However, synovial fibroblasts from obese OA patients were found to secrete greater amounts of the pro-inflammatory cytokine IL-6, compared to those from normal-weight patients (p < 0.05), which reflected the greater levels of IL-6 detected in the synovial fluid of the obese OA patients. Investigation into the inflammatory mechanism demonstrated that IL-6 secretion from synovial fibroblasts was induced by chondrocyte-derived IL-6. Furthermore, this IL-6 inflammatory response, mediated by chondrocyte-synovial fibroblast cross-talk, was enhanced by the obesity-related adipokine leptin. This study suggests that obesity enhances the cross-talk between chondrocytes and synovial fibroblasts via raised levels of the pro-inflammatory adipokine leptin, leading to greater production of IL-6 in OA patients.

Topics: Aged; Body Mass Index; Cell Communication; Chondrocytes; Female; Fibroblasts; Humans; Interleukin-6; Interleukin-8; Leptin; Male; Middle Aged; Models, Biological; Obesity; Osteoarthritis; Synovial Fluid; T-Lymphocyte Subsets

Osteoarthritis (OA) is a chronic degenerative joint disease. An increasing number of studies point to the role of microRNAs (miRNAs or miRs) in the pathogenesis of OA. An earlier study suggested that miR‑27b was associated with OA; however, the precise mechanisms regarding the involvement of the miR‑27 in the progression of OA remain unclear. In the present study, we first analyzed the effects of miR‑27 on OA. In vitro, the degree of miR‑27 expression was decreased in chondrocytes obtained from patients with OA. Transfection with miR‑27 mimic increased the viability of CH8 cells and induced the expression of type-II collagen, type-X collagen, glycosaminoglycan (GAG) and aggrecan (ACAN). The results of luciferase activity assay revealed that miR‑27 directly targeted the 3'-untranslated region (3'-UTR) of leptin. The results of western blot analysis and ELISA indicated that the concentration of leptin was decreased after the CH8 cells were transfected with miR‑27 mimic. In vivo, a rat model of OA was established by anterior cruciate ligament transection (ACLT). When the rats with OA were injected with miR‑27 lentiviral overexpression vector, the results of ELISA revealed that the levels of interleukin (IL)-6 and IL-8 were decreased. The results of western blot analysis revealed that matrix metalloproteinase (MMP)-9 and MMP-13 expression levels were decreased, and the nuclear factor-κB (NF-κB) pathway was inhibited. On the whole, our results suggest that the upregulation of miR‑27 inhibits the pathogenesis of OA by targeting leptin and inhibiting the NF-κB signaling pathway. Thus, miR‑27 exerts protective effects against OA.

Topics: Animals; Cell Line; Cells, Cultured; Chondrocytes; Gene Expression Regulation; Humans; Leptin; MicroRNAs; NF-kappa B; Osteoarthritis; Rats; Signal Transduction

Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD-fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD-induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice.

Topics: Animals; Biomarkers; Biopsy; Blood Glucose; Body Weight; Cartilage, Articular; Diet, High-Fat; Disease Models, Animal; Immunohistochemistry; Insulin; Leptin; Metabolome; Mice; Osteoarthritis; ROC Curve

Osteoarthritis (OA) is a chronic systemic musculoskeletal disorder involving inflammation, immunity, and metabolic alterations. OA is commonly regarded as non-inflammatory disease; still inflammation is recognized as contributing to the symptoms and progression of OA. New evidence suggests that adipokines are involved in the pathophysiology of OA and might modulate the production of inflammatory mediators including in immune cells. However, the role of immune component in osteoarthritis is still poorly investigated. To gain further insights into the interaction of immune cells in OA and the role of adipokines on these cells, we performed experiments aimed to determine the cytokine profile in activated CD4

Topics: Adiponectin; Adult; Aged; Aged, 80 and over; Case-Control Studies; CD4-Positive T-Lymphocytes; Chondrocytes; Coculture Techniques; Humans; Leptin; Lipocalin-2; Osteoarthritis; Primary Cell Culture

To assess the differential features of marrow adiposity between osteoarthritis (OA) and osteoporosis (OP) in postmenopausal women using water/fat MRI.. This cross-sectional study included 97 postmenopausal women (OA [n = 25], OA + osteopenia [n = 27], OA + OP [n = 23], and OP groups [n = 22]). Water/fat MRI, dual-energy x-ray absorptiometry and biochemical analysis were performed to assess vertebral marrow fat fraction, bone mineral density, and bone biomarkers, respectively. Harris Hip Score was recorded to evaluate hip function.. There were significant differences in marrow fat content among the OA, OA + osteopenia, and OA + OP groups, between OP and OA participants with normal bone mass or osteopenia (all P < 0.05); no significant difference was observed between OA + OP and OP groups. Serum levels of leptin and β-Crosslaps in OA with normal bone mass and osteopenic OA groups were higher than in OP group. Marrow fat fraction was inversely correlated with Harris Hip Score (r = -0.371, P = 0.013), bone mineral density (r = -0.554, P = 0.009) and leptin levels (r = -0.610, P < 0.001). In multivariate regression analysis, marrow fat fraction was found to have a consistent and unchanged inverse association with leptin levels (Sβ = -0.311, P = 0.002) and bone mineral density (Sβ =  -0.265, P = 0.006) after adjusting for age, years since menopause, and body mass index.. Postmenopausal OA with OP have a phenotype with higher marrow adiposity. OA and OP could coexist, for the presence of a specific subgroup of OA with increased marrow fat accumulation and high risk of developing OP.

Topics: Absorptiometry, Photon; Adiposity; Aged; Biomarkers; Bone Density; Bone Marrow; Cross-Sectional Studies; Female; Humans; Leptin; Magnetic Resonance Imaging; Middle Aged; Osteoarthritis; Osteoporosis, Postmenopausal; Postmenopause

Increased mitogen-activated protein kinase (MAPK) activity has been found in human osteoarthritis (OA). Dual specificity protein phosphatase 19 (DUSP19), a member of mitogen-activated protein kinase (MAPK) phosphatases (MKPs), controls the activity of various MAPKs. This study was aimed to explore the function of DUSP19 during OA pathogenesis. Here, OA and healthy control data were downloaded from the NCBI Gene Expression Omnibus database (GSE57218). Forty-five patients with OA and 25 healthy donors were enrolled in this study. A rat OA model was induced by anterior cruciate ligament transection. Primary cultured chondrocytes were treated with leptin (10 ng mL(-1)). Cell survival, cell apoptosis and reactive oxygen species (ROS) were identified by CCK-8 and flow cytometry, respectively. In the cartilage of OA patients, DUSP19 was expressed in a lower level than in the cartilage of healthy control. The DUSP19 level was negatively correlated with leptin, which was confirmed by experiments in the rat OA model. Moreover, cell apoptosis and JNK activation in the rat cartilage were increased with the increasing of leptin levels and the decreasing of DUSP19 mRNA levels. In primary culture chondrocytes, exogenous leptin suppressed DUSP19 expression. The ectopic expression of DUSP19 significantly ameliorated leptin-induced apoptosis in damaged chondrocytes, accompanied by the reduced production of ROS. Moreover, the activity of JNK stimulated by leptin was suppressed by DUSP19 overexpression. The present study indicated that DUSP19, a downstream of leptin, inhibited apoptosis of chondrocytes through dephosphorylating JNK.

Topics: Adult; Aged; Animals; Apoptosis; Cartilage, Articular; Cell Survival; Chondrocytes; Disease Models, Animal; Dual-Specificity Phosphatases; HEK293 Cells; Humans; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Leptin; Male; Middle Aged; Osteoarthritis; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Signal Transduction; Tumor Necrosis Factor-alpha

Reactive oxygen species (ROS)-induced chondrocytes apoptosis plays a key role in osteoarthritis (OA) pathogenesis. Uncoupling protein 4 (UCP4) can protect cells against oxidative stress via reducing ROS production and cell apoptosis. Here, silencing of UCP4 in primary chondrocytes significantly inhibited cell survival, but induced ROS production and cell apoptosis. UCP4 mRNA of cartilage tissues was decreased in osteoarthritis patients, which was negatively correlated with synovial fluid (SF) leptin concentration. Moreover, leptin treatment (5, 10 and 20 ng/ml) of primary cultured chondrocytes significantly decreased mRNA and protein levels of UCP4, but increased ROS production and cell apoptosis in a dose-dependent manner. The effects of leptin treatment (20 ng/ml) on chondrocytes was partially reversed by ectopic expression of UCP4. More importantly, intraarticularly injection of UCP4 adenovirus remarkably alleviate OA progression and cell apoptosis in a rat OA model induced by anterior cruciate ligament transection (ACLT). In conclusion, UCP4, whose expression was suppressed by leptin, may be involved in the ROS production and apoptosis of chondrocytes, thus contributing to the OA pathogenesis.

Topics: Adult; Aged; Animals; Apoptosis; Cartilage, Articular; Cell Proliferation; Cells, Cultured; Chondrocytes; Down-Regulation; Humans; Ion Channels; Leptin; Male; Membrane Potential, Mitochondrial; Membrane Transport Proteins; Middle Aged; Mitochondrial Proteins; Mitochondrial Uncoupling Proteins; Osteoarthritis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA Interference; RNA, Messenger; RNA, Small Interfering

Emerging data has suggested a high prevalence of osteoarthritis (OA) among obese people. As an important adipokine secreted by white adipose tissue, leptin may be a key mediator in the progression of OA. Leptin exerts a catabolic effect on OA cartilage by increasing the production of metalloproteinase (MMP) enzymes, and contributes to apoptosis in chondrocytes. The current study aimed to explore the role of leptin on the apoptosis of chondrocytes in OA, and its underlying mechanisms. In the in vitro model of OA used in the present study, administration of exogenous leptin induced the generation of reactive oxygen species (ROS) and apoptosis in chondrocytes. It has been demonstrated that leptin is associated with the pathogenesis of OA via the Janus kinase 2 (JAK2)‑signal transducer and activator of transcription 3 (STAT3) signaling pathway, and data gathered in the present study demonstrated that suppression of this signaling pathway using a JAK2 inhibitor, AG490, significantly ameliorated leptin‑induced apoptosis in damaged chondrocytes in vitro, and reduced the generation of ROS. Furthermore, the protein expression levels of MMP‑13 and B‑cell lymphoma 2‑associated X protein were downregulated in the AG490‑treated group. The results of the present study may provide insight into the underlying molecular mechanism by which leptin induces apoptosis in chondrocytes. These findings indicated the importance of leptin as a therapeutic target for the treatment of OA in the overweight population.

Topics: Animals; Anterior Cruciate Ligament; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Cells, Cultured; Chondrocytes; Disease Models, Animal; Down-Regulation; Janus Kinase 2; Leptin; Male; Matrix Metalloproteinase 13; Osteoarthritis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; STAT3 Transcription Factor; Tyrphostins

Leptin has been found highly expressed in human osteoarthritis. We aimed to explore the possible effects and mechanisms of leptin on the apoptosis and autophagy of chondrocytes during osteoarthritis pathogenesis.. Gene expression profile from osteoarthritis affected and preserved cartilage were downloaded from NCBI's Gene Expression Omnibus database (GSE57218). Lysyl oxidase-like 3 (LOXL3) mRNA expression in cartilage tissues and leptin concentration in joint synovial fluid (SF) was measured in samples from 45 osteoarthritis patients and 25 healthy donors by real-time PCR and radioimmunoassay, respectively. Rat osteoarthritis model was induced by anterior cruciate ligament transection (ACLT). The expression of apoptosis regulators and autophagy markers were detected by Western blot. Cell survival and cell apoptosis were identified by CCK-8 and flow cytometry, respectively.. Re-analysis on GSE57218 indicated that LOXL3 mRNA was upregulated in osteoarthritis affected cartilage. LOXL3 mRNA was upregulated in osteoarthritis patients, which was positively correlated with SF leptin concentration. Similar results were obtained in rat osteoarthritis model. Moreover, ACLT surgery led to a significant increase in the protein levels of cleaved caspase 3, and a notable decrease in the protein levels of Bcl-2, LC3 II/LC3 I and Beclin1. Silencing of LOXL3 in ACLT and leptin treated primary chondrocytes significantly inhibited cell apoptosis, and promoted cell proliferation and autophagy. Moreover, overexpression of LOXL3 remarkably inhibited autophagy of chondrocytes via activating mTORC1.. LOXL3, a downstream of leptin, stimulated the apoptosis, but inhibited the autophagy of chondrocytes. LOXL3 is a potential therapy target for osteoarthritis.

Topics: Animals; Apoptosis; Autophagy; Cartilage, Articular; Chondrocytes; Humans; Leptin; Osteoarthritis; Protein-Lysine 6-Oxidase; Rats

Body weight is a component of the mechanical theory of OA (osteoarthritis) pathogenesis. Obesity was also found to be a risk factor for digital OA involving non-weight-bearing joints, which suggested that metabolism influences the occurrence and progression of OA. The metabolic origin of OA has been partially attributed to the involvement of adipokines, such as leptin, the levels of which are significantly and positively correlated with cartilage degeneration in OA patients. However, the mechanisms by which leptin-induced cartilage degeneration occurs are poorly understood. The discovery of chondrogenic progenitor cells (CPCs) opened up new opportunities for investigation. Investigating the effects of leptin on differentiation and proliferation in CPCs would increase our understanding of the roles played by leptin in the aetiology and development of OA. Here, CPCs were harvested using single-cell sorting from rat cartilage tissues to obtain mesenchymal stem-like cells, which possess clonogenicity, proliferation and stemness. High doses of leptin decreased the ability of the CPCs to migrate, inhibited their chondrogenic potential and increased their osteogenic potential, suggesting that leptin changes differentiation fates in CPCs. High doses of leptin induced cell cycle arrest and senescence in CPCs by activating the p53/p21 pathway and inhibiting the Sirt1 pathway. Inhibiting the Sirt1 pathway accelerated cartilage senescence in knockout (KO) mice. Activating the leptin pathway induced higher Ob-Rb expression and was significantly correlated with cartilage degeneration (lower levels of Coll-2) and tissue senescence (higher levels of p53/p21 and lower levels of Sirt1) in OA patients, suggesting that leptin-induced CPCs senescence contributes to the development of OA. Taken together, our results reveal new links between obesity and cartilage damage that are induced by leptin-mediated effects on cell behaviour and senescence.

Topics: Animals; Cartilage; Cell Cycle Checkpoints; Cell Differentiation; Cell Movement; Cells, Cultured; Cellular Senescence; Chondrocytes; Chondrogenesis; Core Binding Factor Alpha 1 Subunit; Cyclin-Dependent Kinase Inhibitor p21; Humans; Leptin; Mice; Mice, Knockout; Middle Aged; Osteoarthritis; Rats; Rats, Sprague-Dawley; Signal Transduction; Sirtuin 1; Stem Cells; Tumor Suppressor Protein p53

The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of fatty acids, adipokines, and body weight on OA following joint injury in an obese mouse model.. Mice were fed high-fat diets rich in various fatty acids (FA) including saturated FAs (SFAs), ω-6 polyunsaturated FAs (PUFAs), and ω-3 PUFAs. OA was induced by destabilising the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic and mechanical factors with OA and wound healing.. Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of ω-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. ω-3 PUFAs significantly enhanced wound repair, SFAs or ω-6 PUFAs independently increased OA severity, heterotopic ossification and scar tissue formation.. Our results indicate that with obesity, dietary FA content regulates wound healing and OA severity following joint injury, independent of body weight, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA.

Topics: Animals; Body Weight; Bone and Bones; Diet, High-Fat; Dietary Fats; Disease Models, Animal; Ear Auricle; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Femur; Leg Injuries; Leptin; Mice; Obesity; Osteoarthritis; Osteoarthritis, Knee; Resistin; Stifle; Synovitis; Tibia; Tibial Meniscus Injuries; Wound Healing; X-Ray Microtomography

Glucocorticoids are powerful anti-inflammatory compounds that also induce the expression of leptin and leptin receptor (Ob-R) in synovial fibroblasts through TGF-βsignalling and Smad1/5 phosphorylation. Compound A (CpdA), a selective glucocorticoid receptor agonist, reduces inflammation in murine arthritis models and does not induce diabetes or osteoporosis, thus offering an improved risk:benefit ratio in comparison with glucocorticoids. Due to the detrimental role of leptin in OA pathogenesis, we sought to determine whether CpdA also induced leptin and Ob-R protein expression as observed with prednisolone.. Human synovial fibroblasts and chondrocytes were isolated from the synovium and cartilage of OA patients after joint surgery. The cells were treated with prednisolone, TGF-β1, TNF-α and/or CpdA. Levels of leptin, IL-6, IL-8, MMP-1 and MMP-3 were measured by ELISA and expression levels of Ob-R phospho-Smad1/5, phospho-Smad2, α-tubulin and glyceraldehyde 3-phosphate dehydrogenase were analysed by western blotting.. CpdA, unlike prednisolone, did not induce leptin secretion or Ob-R protein expression in OA synovial fibroblasts. Moreover, CpdA decreased endogenous Ob-R expression and down-regulated prednisolone-induced leptin secretion and Ob-R expression. Mechanistically, CpdA, unlike prednisolone, did not induce Smad1/5 phosphorylation. CpdA, similarly to prednisolone, down-regulated endogenous and TNF-α-induced IL-6, IL-8, MMP-1 and MMP-3 protein secretion. The dissociative effect of CpdA was confirmed using chondrocytes with no induction of leptin secretion, but with a significant decrease in IL-6, IL-8, MMP-1 and MMP-3 protein secretion.. CpdA, unlike prednisolone, did not induce leptin or Ob-R in human OA synovial fibroblasts, thereby demonstrating an improved risk:benefit ratio.

Topics: Aged; Aged, 80 and over; Blotting, Western; Chondrocytes; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Glyceraldehyde-3-Phosphate Dehydrogenases; Humans; Interleukin-6; Interleukin-8; Leptin; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 3; Middle Aged; Osteoarthritis; Prednisolone; Receptors, Glucocorticoid; Receptors, Leptin; Smad Proteins, Receptor-Regulated; Synovial Membrane; Transforming Growth Factor beta1; Tubulin; Tumor Necrosis Factor-alpha

Osteoarthritis (OA) in obese individuals is often attributed to joint loading. However, a subtype of OA, Metabolic OA, may be due to obesity-related intrinsic factors but remains to be evaluated experimentally against a known OA progression model.. To evaluate if obesity contributes to OA onset using a high fat/high sucrose diet-induced obesity (DIO) model with anterior cruciate ligament-transected rats (ACL-X).. Sprague Dawley rats (n = 33) consumed high fat/high sucrose or chow diets for 12 weeks, were randomized to one of three groups: a unilateral ACL-X group, sham surgery group, or naïve non-surgical group. These animals were followed for an additional 16 weeks. At sacrifice, body composition, knee joint Modified Mankin scores, and 27 serum and synovial fluid cytokines and adipokines were measured.. Experimental limbs of obese ACL-X, obese Sham, and lean ACL-X animals had similar Modified Mankin scores that were greater than those obtained from lean Sham and naïve animals. Obese contralateral limbs had similar OA damage as ACL-X and Sham limbs of obese and ACL-X limbs of lean animals. Obese contralateral limb Modified Mankin scores had a strong correlation (r = 0.75, P < 0.001) with body fat percentage. Serum leptin and synovial fluid IP10/CXCL10 best described Modified Mankin scores in contralateral limbs of obese animals.. Mechanical factors produced OA damage in experimental limbs, as expected. Interestingly, OA damage in obese contralateral limbs was similar to mechanically perturbed limbs, suggesting that obesity may induce OA in a non-mechanical manner.

Topics: Adipokines; Adipose Tissue; Animals; Anterior Cruciate Ligament Injuries; Arthritis, Experimental; Body Composition; Cytokines; Diet, High-Fat; Leptin; Male; Obesity; Osteoarthritis; Rats, Sprague-Dawley; Synovial Fluid

There is compelling evidence in humans that peripheral endocannabinoid signaling is disrupted in obesity. However, little is known about the corresponding central signaling. Here, we have investigated the relationship between gender, leptin, body mass index (BMI) and levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the serum and cerebrospinal fluid (CSF) of primarily overweight to obese patients with osteoarthritis.. Patients (20 females, 15 males, age range 44-78 years, BMI range 24-42) undergoing total knee arthroplasty for end-stage osteoarthritis were recruited for the study. Endocannabinoids were quantified by liquid chromatography - mass spectrometry. AEA and 2-AG levels in the serum and CSF did not correlate with either age or BMI. However, 2-AG levels in the CSF, but not serum, correlated negatively with CSF leptin levels (Spearman's ρ -0.48, P=0.0076, n=30). No such correlations were observed for AEA and leptin.. In the patient sample investigated, there is a negative association between 2-AG and leptin levels in the CSF. This is consistent with pre-clinical studies in animals, demonstrating that leptin controls the levels of hypothalamic endocannabinoids that regulate feeding behavior.

Topics: Adult; Aged; Arachidonic Acids; Arthroplasty, Replacement, Knee; Body Mass Index; Chromatography, Liquid; Endocannabinoids; Female; Glycerides; Humans; Leptin; Male; Mass Spectrometry; Middle Aged; Obesity; Osteoarthritis; Polyunsaturated Alkamides

Alterations in leptin expression contributes to the progression of various diseases, including cancers. This meta-analysis investigated the clinical significance of leptin levels in osteoarthritis (OA) patients, with the goal of building a leptin-based diagnostic criterion for OA.. Multiple scientific databases in English and Chinese languages, such as the Cochrane Library Database, CINAHL, Chinese Biomedical (CBM), EMBASE, PubMed, and Web of Science, were exhaustively searched, without any language restrictions, to identify high-quality studies relevant to leptin and OA. Version 12.0 STATA software was used for data analysis. We used odds ratios (OR) and 95% confidence intervals (CI) to test the correlation between serum leptin levels and OA progression.. A total of 11 clinical studies were finally selected for their high quality and relevance to the topic in this meta-analysis. The 11 case-control studies contained a combined total of 3,625 subjects. The meta-analysis results showed that leptin expression was significantly increased in OA patients, compared with the controls (SMD = 0.87, 95%CI: 0.72-1.02, P < 0.001), and there was also a strong association between leptin expression levels and gender (SMD = 8.55, 95%CI: 4.74-12.35, P < 0.001). In ethnicity-stratified subgroup analysis, all the study populations, irrespective of ethnicity, showed remarkably high leptin expression levels in females and in OA patients (all P < 0.05), compared to their respective counterparts.. The present study revealed that increased leptin expression levels are associated with disease severity in OA patients, especially among the female OA patients. Based on our results, we propose that leptin level may be a useful biomarker for the assessment of the clinical status in OA patients.

Topics: Aged; Female; Humans; Leptin; Male; Middle Aged; Osteoarthritis; Publication Bias

Survivin is an independent prognostic factor for joint destruction in rheumatoid arthritis (RA). However, the expression and function of survivin in RA synoviocytes remain unclear. We certified the expression of survivin in RA synovial tissues and performed the experiment using RA fibroblast-like synoviocytes (RA-FLS) treated with siRNA. As a result, the expression levels of wild type (WT) survivin and the 2B splice variants in RA synovial tissues were higher than those in osteoarthritis tissue samples, and, these variants were highly expressed in RA-FLS. The expression levels of survivin-WT and -2B in the RA-FLS were upregulated by PDGF. Treatment with siRNA against survivin-2B led to decreased viability of PDGF-treated RA-FLS due to cell cycle suppression and apoptosis promotion, while the siRNA against all survivin isoforms did not affect the viability. Moreover, an overexpression of survivin-2B in RA-FLS led to cell proliferation through cell cycle activation and by conferring resistance to apoptosis. In conclusion, survivin-2B has an important role in RA-FLS proliferation. These data suggest that survivin-2B might contribute to rheumatoid synovial hyperplasia, and have the potential as a novel therapeutic target for RA.

Topics: Aged; Apoptosis; Arthritis, Rheumatoid; Becaplermin; Cell Proliferation; Cell Survival; Cells, Cultured; Female; Fibroblasts; Humans; Inhibitor of Apoptosis Proteins; Interleukin-1beta; Leptin; Male; Middle Aged; Osteoarthritis; Protein Isoforms; Proto-Oncogene Mas; Proto-Oncogene Proteins c-sis; RNA Splicing; RNA, Small Interfering; Survivin; Synovial Membrane; Tumor Necrosis Factor-alpha

Bone morphogenetic proteins (BMPs) play positive roles in cartilage development, but they can barely be detected in healthy articular cartilage. However, recent evidence has indicated that BMPs could be detected in osteoarthritic and damaged cartilage and their precise roles have not been well defined. Extremely high amounts of leptin have been reported in obese individuals, which can be associated with osteoarthritis (OA) development. The aim of this study was to investigate whether BMPs could be induced in human primary chondrocytes during leptin-stimulated OA development and the underlying mechanism. We found that expression of BMP-2 mRNA, but not BMP-4, BMP-6, or BMP-7 mRNA, could be increased in human primary chondrocytes under leptin stimulation. Moreover, this BMP-2 induction was mediated through transcription factor-signal transducer and activator of transcription (STAT) 3 activation via JAK2-ERK1/2-induced Ser727-phosphorylation. Of note, histone deacetylases (HDACs) 3 and 4 were both involved in modulating leptin-induced BMP-2 mRNA expression through different pathways: HDAC3, but not HDAC4, associated with STAT3 to form a complex. Our results further demonstrated that the role of BMP-2 induction under leptin stimulation is to increase collagen II expression. The findings in this study provide new insights into the regulatory mechanism of BMP-2 induction in leptin-stimulated chondrocytes and suggest that BMP-2 may play a reparative role in regulating leptin-induced OA development.

Topics: Aged; Aged, 80 and over; Bone Morphogenetic Protein 2; Cells, Cultured; Chondrocytes; Collagen Type II; Female; Gene Expression Regulation; Histone Deacetylases; Humans; Janus Kinase 2; Leptin; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Osteoarthritis; Repressor Proteins; RNA, Messenger; STAT3 Transcription Factor

Serum leptin measures are associated with radiographic knee osteoarthritis, but no studies have examined leptin levels with respect to different measures of knee joint damage from MRI.. Participants in the Michigan Study of Women's Health Across the Nation underwent bilateral knee MRIs at follow-up visit 11 for assessment of cartilage defects, bone marrow lesions, osteophytes, meniscal tears, synovitis and joint effusion. Serum leptin measures were available from baseline, follow-up visits 1 and 3-7.. Baseline serum leptin levels were associated with greater odds of having more severe knee joint damage at follow-up visit 11 after adjustment for age, smoking status, menopause status and body mass index residuals. The greatest effect was observed for osteophytes; a 5 ng/ml increase in baseline leptin was associated with 24% higher odds of having larger osteophytes (95% CI 1.17 to 1.32). Correlations with baseline serum leptin were greatest for MRI-assessed osteophytes (r=0.41), followed by effusion (r=0.32), synovitis (r=0.30), cartilage defects (r=0.28), bone marrow lesions (r=0.24) and meniscal abnormalities (r=0.21).. Leptin levels 10 years prior to MRI assessment were associated with the presence of cartilage defects, bone marrow lesions, osteophytes, meniscal tears, synovitis and effusion among a population of middle-aged women. Understanding the role that leptin plays in the joint degradation process is critical for development of more targeted interventions for osteoarthritis.

Topics: Adult; Female; Humans; Knee Joint; Leptin; Magnetic Resonance Imaging; Middle Aged; Osteoarthritis; Prevalence

Cell-based therapies have recently been proposed for the treatment of degenerative articular pathologies, such as early osteoarthritis, with an emphasis on autologous mesenchymal stem cells (MSCs), as an alternative to terminally differentiated cells. In this study, we performed a donor-matched comparison between infrapatellar fat pad MSCs (IFP-MSCs) and knee subcutaneous adipose tissue stem cells (ASCs), as appealing candidates for cell-based therapies that are easily accessible during surgery. IFP-MSCs and ASCs were obtained from 25 osteoarthritic patients undergoing total knee replacement and compared for their immunophenotype and differentiative potential. Undifferentiated IFP-MSCs and ASCs displayed the same immunophenotype, typical of MSCs (CD13+/CD29+/CD44+/CD73+/CD90+/CD105+/CD166+/CD31-/CD45-). IFP-MSCs and ASCs showed similar adipogenic potential, though undifferentiated ASCs had higher LEP expression compared to IFP-MSCs (p<0.01). Higher levels of calcified matrix (p<0.05) and alkaline phosphatase (p<0.05) in ASCs highlighted their superior osteogenic commitment compared to IFP-MSCs. Conversely, IFP-MSCs pellets showed greater amounts of glycosaminoglycans (p<0.01) and superior expression of ACAN (p<0.001), SOX9, COMP (p<0.001) and COL2A1 (p<0.05) compared to ASCs pellets, revealing a superior chondrogenic potential. This was also supported by lower COL10A1 (p<0.05) and COL1A1 (p<0.01) expression and lower alkaline phosphatase release (p<0.05) by IFP-MSCs compared to ASCs. The observed dissimilarities between IFP-MSCs and ASCs show that, despite expressing similar surface markers, MSCs deriving from different fat depots in the same surgical site possess specific features. Furthermore, the in vitro peculiar commitment of IFP-MSCs and ASCs from osteoarthritic donors towards the chondrogenic or osteogenic lineage may suggest a preferential use for cartilage and bone cell-based treatments, respectively.

Topics: Adipogenesis; Adipose Tissue; Aged; Aged, 80 and over; Aggrecans; Alkaline Phosphatase; Antigens, CD; Calcium; Cartilage Oligomeric Matrix Protein; Cells, Cultured; Chondrogenesis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type X; Female; Glycosaminoglycans; Humans; Leptin; Male; Mesenchymal Stem Cells; Middle Aged; Osteoarthritis; Osteogenesis; Patella; SOX9 Transcription Factor; Tissue Donors

Bone remodelling and increased subchondral densification are important in osteoarthritis (OA). Modifications of bone vascularisation parameters, which lead to ischemic episodes associated with hypoxic conditions, have been suspected in OA. Among several factors potentially involved, leptin and dickkopf-related protein 2 (DKK2) are good candidates since they are up-regulated in OA osteoblasts (Obs). Therefore, in the present study, we investigated the hypothesis that hypoxia may drive the expression of leptin and DKK2 in OA Obs.. Obs from the sclerotic portion of OA tibial plateaus were cultured either under 20% or 2% oxygen tension in the presence or not of 50 nM of 1,25-dihydroxyvitamin D3 (VitD3). The expression of leptin, osteocalcin, DKK2, hypoxia-inducible factors (Hif)-1α and -2α was measured by real-time polymerase chain reaction and leptin production by enzyme-linked immunosorbent assay (ELISA). The expression of Hif-1α, Hif-2α, leptin and DKK2 was reduced using silencing (si) RNA technique. Signalling pathway of hypoxia-induced leptin was investigated by western blotting and mitogen-activated protein kinase (MAPK) inhibitors.. As expected, hypoxia stimulated the expression of Hif-1 and Hif-2. The expression of leptin and DKK2 in Obs was also stimulated 7-fold and 1.8-fold respectively (p<0.05) under hypoxia. Interestingly, whereas VitD3 stimulated leptin and DKK2 expression 2- and 4.2-fold under normoxia, it further stimulated it to 28- and 6.2-fold under hypoxia (p<0.05). The hypoxia-induced leptin production was confirmed by ELISA, particularly in presence of VitD3 (p<0.02). Compared to Obs incubated in the presence of siScramble RNAs, siHif-2α inhibited VitD3-stimulated leptin mRNA and protein levels by 70% (p=0.004) and 60% (p<0.02), respectively while it failed to significantly alter the expression of DKK2. SiHif-1α has no effect on these genes. Immunoblotting showed that VitD3 greatly stabilized Hif-2α under hypoxic condition. The increase in leptin expression under hypoxia was also regulated, in addition to the role of Hif-2α, by p38 MAPK (p<0.03) and PI 3-kinase (p<0.05). Finally, we demonstrated that the expression of leptin and DKK2 were not related to each other under hypoxia.. Hypoxic conditions via Hif-2 regulation trigger Obs to produce leptin particularly under VitD3 stimulation whereas DKK2 is mainly regulated by VitD3 rather than hypoxia.

Topics: Aged; Basic Helix-Loop-Helix Transcription Factors; Bone and Bones; Cell Hypoxia; Cells, Cultured; Female; Gene Expression; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Osteoarthritis; Osteoblasts; Osteocalcin; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Vitamin D; Vitamins

Study of 130 osteoarthrosis patients revealed high serum level of leptin in 42 (32.3 %) patients including 9 males and 33 females. Osteoarthrosis patients with high serum leptin level are characterized by more severe course of the disease.

Topics: Adult; Aged; Female; Humans; Industry; Leptin; Male; Middle Aged; Occupational Diseases; Osteoarthritis; Predictive Value of Tests; Russia; Severity of Illness Index; Workforce

Increasingly, an inflammatory modulating effect of adipokines within synovial joints is being recognized. To date, there has been no work examining a potential association between the presence of adipokines in the shoulder and patient-reported outcomes. This study undertakes an investigation assessing these potential links.. 50 osteoarthritis patients scheduled for shoulder surgery completed a pre-surgery questionnaire capturing demographic information including validated, patient-reported function (Disabilities of the Arm, Shoulder, and Hand questionnaire) and pain (Short Form McGill Pain Questionnaire) measures. Synovial fluid (SF) samples were analyzed for leptin, adiponectin, and resistin levels using Milliplex MAP assays. Linear regression modeling was used to assess the association between adipokine levels and patient-reported outcomes, adjusted for age, sex, BMI, and disease severity.. 54% of the cohort was female (n = 27). The mean age (SD) of the sample was 62.9 (9.9) years and the mean BMI (SD) was 28.1 (5.4) kg/m(2). From regression analyses, greater SF leptin and adiponectin levels, but not regarding resistin, were found to be associated with greater pain (p < 0.05). Adipokine levels were not associated with functional outcome scores.. The identified association between shoulder-derived SF leptin and adiponectin and shoulder pain is likely explained by the pro-inflammatory characteristics of the adipokines and represents potentially important therapeutic targets.

Topics: Adiponectin; Aged; Body Mass Index; Female; Humans; Inflammation; Leptin; Male; Middle Aged; Obesity; Osteoarthritis; Resistin; Shoulder Pain; Surveys and Questionnaires; Synovial Fluid

Leptin has been suspected to contribute to the development of osteoarthritis (OA). However, this hypothesis has not been tested in large-scale hand OA cohorts. Our study aimed to determine whether there is a cross-sectional relationship between serum leptin levels and hand OA in a population-based sample of US adults.. We used the Third National Health and Nutrition Examination Survey (NHANES III), a national cross-sectional population-based survey, to study the relationship between hand OA and serum leptin concentration. We applied previously established classification criteria for hand OA. Patients with rheumatoid arthritis were excluded. Potential confounders included sex, body mass index, the presence of polyarticular OA, diabetes, and total cholesterol. We estimated unadjusted mean leptin concentration by hand OA status and by all confounders. We further developed a linear regression model to assess mean leptin levels, adjusted for appropriate confounders.. Of 2,477 subjects in the NHANES III sample that had a hand examination and did not have rheumatoid arthritis, 1,056 (42.6%) had a leptin measurement and were included in the analysis. Subjects with and without leptin measurement had similar demographic characteristics. We did not find any significant differences in mean serum leptin levels in subjects with symptomatic hand OA (7.38 ng/ml in males (95% confidence interval (CI) = 5.31, 9.46) and 21.55 ng/ml in females (95% CI = 17.08, 26.02)), asymptomatic hand OA (6.69 ng/ml in males (95% CI = 5.19, 8.18) and 17.09 ng/ml in females (95% CI = 15.00, 19.18)), and no hand OA (8.22 ng/ml in males (95% CI = 7.47, 8.97) and 20.77 ng/ml in females (95% CI = 18.01, 23.53)) in the unadjusted analysis. In a multivariable linear regression model that included variables of hand OA status, age, race/ethnicity, and obesity status, we found no statistically significant association between serum leptin and hand OA status.. In this cross-sectional study of a large representative US cohort, we did not find any evidence to support the hypothesis that serum leptin is associated with hand OA.

Topics: Aged; Aged, 80 and over; Body Mass Index; Cross-Sectional Studies; Female; Hand; Humans; Leptin; Male; Middle Aged; Nutrition Surveys; Osteoarthritis; United States

Obesity is an important risk factor for the development and progression of osteoarthritis (OA). Recently, the paradigm that obesity predisposes people to OA because of extra-mechanical loading only has shifted to the paradigm that metabolic factors (adipokines) are also involved in the pathophysiology of OA. In a cross-sectional study in the previous issue of Arthritis Research & Therapy, Massengale and colleagues investigated the association between one of the adipokines - leptin - and hand OA. Hand joints are an ideal target to investigate the role of adipokines since they are not weight-bearing. Interestingly, no association with OA was found, bringing into question a metabolic, rather than a mechanical, explanation for the association between obesity and OA.

Topics: Female; Humans; Leptin; Male; Osteoarthritis

Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain.. In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain.. The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m(2) for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R(2) = 0.00-0.04 unadjusted analysis, all p-values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R(2) = 0.36 unadjusted analysis, p-values≤0.04).. In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain.

Topics: Age Factors; Aged; Body Mass Index; Cohort Studies; Coronary Artery Disease; Female; Hand; Humans; Insect Hormones; Leptin; Linear Models; Male; Middle Aged; Musculoskeletal Pain; Oligopeptides; Osteoarthritis; Pyrrolidonecarboxylic Acid; Radiography; Resistin

To investigate the effects of 5-Aza-CdR (methylation transferase inhibitor)on the expression levels of leptin gene in chondrocytes and methylation states of leptin promoter region between osteoarthritis (OA) group and control.. The chondrocytes in osteoarthritis group were treated with 5-Aza-CdR with different doses and time-points, and the expression level of leptin was detected by real-time polymerase chain reaction for picking up the optimum dose and time-point. Next, the chondrocytes in 5 osteoarthritis patients and 5 control patients (amputation due to severe trauma) were treated with 5-Aza-CdR. Lastly, leptin mRNA expression levels in the four groups osteoarthritis and control chondrocytes treated with/without 5-Aza-CdR were measured by real-time PCR and the methylation state of promoter region (-280 - +79) was detected by epitope quantitative DNA methylation analysis.. (1) After treating the chondrocytes in OA groups with 10 µmol/L 5-Aza-CdR for 72 h, the mRNA expression levels of leptin were increased significantly. (2) The mRNA expression levels of leptin were significantly different among the four groups (P < 0.05), and the chondrocytes in osteoarthritis groups treated with 5-Aza-CdR showed a marked induction of leptin mRNA expression. (3) Analysis of quantitative methylation data using an unsupervised hierarchical clustering algorithm, showed that methylation patterns of leptin promoter was different between control and osteoarthritis chondrocyte treated with/without 5-Aza-CdR.. Demethylation of leptin promoter might up-regulate leptin gene expression level and it might contribute to osteoarthritis.

Topics: Adult; Aged; Azacitidine; Case-Control Studies; Cells, Cultured; Chondrocytes; CpG Islands; DNA Methylation; Female; Humans; Leptin; Male; Middle Aged; Osteoarthritis; Promoter Regions, Genetic

To investigate the association between baseline serum adipokines levels-leptin, adiponectin and resistin-and long-term progression of hand osteoarthritis (HOA).. Baseline and 6-year radiographs of 164 patients (mean age 60 years, 81% women) with HOA (defined as a Kellgren and Lawrence score ≥2 in at least two hand joints) were assessed for joint space narrowing (JSN) in 32 hand joints using the Osteoarthritis Research Society International atlas. Progression was defined as a change in the sum of the JSN score above the smallest detectable change of 2, reflecting change above measurement error. Serum adipokines were measured at baseline and patients were categorised by adipokine tertiles. RRs (and 95% CI) of HOA progression for patients in the second and third tertiles were calculated relative to the first tertile, using generalised estimating equations. Adjustments were made for age, sex and body mass index.. Patients in the two highest tertiles of adiponectin had a decreased risk of 70% (RR=0.3 (0.2 to 0.7)) for HOA progression in comparison with patients in the lowest tertile. Leptin and resistin levels were not associated with progression.. Adiponectin levels are associated with progression of HOA, suggesting that adiponectin may be involved in the pathophysiology of OA.

Topics: Adipokines; Adiponectin; Adult; Aged; Biomarkers; Disease Progression; Female; Follow-Up Studies; Hand Joints; Humans; Leptin; Male; Middle Aged; Osteoarthritis; Radiography; Resistin; Severity of Illness Index

Although extensive evidence support the key role of adipokines in cartilage homeostasis, contradictory data have been found for their expression and their effects in chondrocytes. This study was then undertaken to determine whether a phenotypic modulation may affect the expression of adipokines and their receptors in human chondrocytes. The expression of leptin, adiponectin and their receptors, as well as cartilage-specific genes was examined in chondrocytes obtained from patients with osteoarthritis either directly after cells harvest or after culture in monolayer or in alginate beads. The results showed major changes in the gene expression pattern after culture in monolayer with a shift from the adipokines to their receptors. Interestingly, this downregulation of adipokines was associated with a loss of chondrocyte phenotype, and chondrocytes recovered a cartilage-like expression profile of leptin and adiponectin when cultured in a tridimensional chondrocyte phenotype-inducing system, but ceased expressing their receptors. Further experiments clearly showed that leptin but not adiponectin promoted the expression of cartilage-specific markers through mitogen-activated protein kinase, Janus kinase and phosphatidylinositol-3 kinase signaling pathways. In conclusion, our data indicate that any phenotypic modulation could affect chondrocyte responsiveness to leptin or adiponectin, and provide evidence for an important role for leptin in regulating the expression of cartilage-specific markers.

Topics: Adipokines; Adiponectin; Aged; Aged, 80 and over; Biomarkers; Cartilage; Cells, Cultured; Chondrocytes; Gene Expression Profiling; Humans; Janus Kinases; Leptin; Middle Aged; Mitogen-Activated Protein Kinases; Osteoarthritis; Phenotype; Phosphatidylinositol 3-Kinases; Receptors, Adipokine; Signal Transduction

Synovial fluid (SF) leptin has been shown to have an association with cartilage degeneration. Our objective was to examine the relationship between different measures of body habitus and SF leptin levels in an end-stage knee osteoarthritis (OA) population. Sixty consecutive patients with knee OA were surveyed prior to surgery for demographic data. Body habitus was assessed with the body mass index (BMI), waist circumference (WC), and waist-hip ratio (WHR). SF and serum samples were analyzed for leptin and adiponectin using specific ELISA. Nonparametric correlations and linear regression modeling was used to identify the relationship between the measures of body habitus and SF leptin levels. Females had greater levels of leptin than males in both the serum and SF. Significant correlations were found between SF leptin levels and BMI and WC (R(2) 0.44 and 0.38, respectively; p < 0.05). Regression modeling showed that female gender and WC were independent predictors of a greater SF leptin level independent of age, BMI, and presence of diabetes (p < 0.05). WC may be a more accurate measure of body habitus than BMI in the relationship between the metabolic effects of adipose tissue and OA.

Topics: Aged; Aged, 80 and over; Body Mass Index; Female; Humans; Knee Joint; Leptin; Linear Models; Male; Middle Aged; Obesity; Osteoarthritis; Sex Factors; Statistics, Nonparametric; Synovial Fluid; Waist Circumference; Waist-Hip Ratio

Leptin is a peptide hormone with a role in bone metabolism and rheumatic diseases. The subchondral bone tissue plays a prominent role in the pathophysiology of osteoarthritis (OA), related to abnormal osteoblast (Ob) differentiation. Although leptin promotes the differentiation of Ob under normal conditions, a role for leptin in OA Ob has not been demonstrated. Here we determined if endogenous leptin produced by OA Ob could be responsible for the expression of the abnormal phenotypic biomarkers observed in OA Ob.. We prepared primary normal and OA Ob from subchondral bone of tibial plateaus removed for knee surgery of OA patients or at autopsy. We determined the production of leptin and of the long, biologically active, leptin receptors (OB-Rb) using reverse transcriptase-polymerase chain reaction, ELISA and Western blot analysis. We determined the effect of leptin on cell proliferation by BrdU incorporation and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and we determined by Western blot analysis phospho 42/44 MAPK (p42/44 Erk1/2) and phospho p38 levels. We then determined the effect of the addition of exogenous leptin, leptin receptor antagonists, inhibitors of leptin signaling or siRNA techniques on the phenotypic features of OA Ob. Phenotypic features of Ob were determined by measuring alkaline phosphatase activity (ALP), osteocalcin release (OC), collagen type 1 production (CICP) and of Transforming Growth Factor-beta1 (TGF-beta1).. Leptin expression was increased approximately five-fold and protein levels approximately two-fold in OA Ob compared to normal. Leptin stimulated its own expression and the expression of OB-Rb in OA Ob. Leptin dose-dependently stimulated cell proliferation of OA Ob and also increased phosphorylated p42/44 Erk1/2 and p38 levels. Inactivating antibodies against leptin reduced ALP, OC, CICP and TGF-beta1 levels in OA Ob. Tyrphostin (AG490) and piceatannol (Pce), inhibitors of leptin signaling, reproduced this effect. Inhibition of endogenous leptin levels using siRNA for leptin or inhibiting leptin signaling using siRNA for OB-Rb expression both reduced ALP and OC about 60%. Exogenous leptin addition stimulated ALP, yet this failed to further increase OC or CICP.. These results suggest that abnormal production of leptin by OA Ob could be responsible, in part, for the elevated levels of ALP, OC, collagen type 1 and TGF-beta1 observed in these cells compared to normal. Leptin also stimulated cell proliferation, and Erk 1/2 and p38 signaling. Taken together, these data suggest leptin could contribute to abnormal osteoblast function in OA.

Topics: Aged; Blotting, Western; Cell Differentiation; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Humans; Leptin; Osteoarthritis; Osteoblasts; Phenotype; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction

The aim of this study was to compare the osteogenic potential and responsiveness to leptin of mesenchymal stem cells (MSCs) from bone marrow between postmenopausal women with osteoarthritis (OA) and osteoporosis (OP). MSCs of the proximal femur from OA and OP donors were cultured under control and different experimental mediums. After verifying the availability of primary cells, their osteogenic potential and responsiveness to leptin were compared between two groups. Similar patterns of cell growth were shown in both OA and OP groups. However, after the sixth passage, the viability of undifferentiated cells decreased more in OP than in OA donors. Under the same osteogenic supplements condition, the mRNA expression of osteogenesis-specific genes, osteocalcin (OC) and alkaline phosphatase (ALP) were higher in OA group. Comparison of bone matrix mineralization was parallel to that of mRNA expression. The level of bone-specific ALP (BAP) was higher in cells from donors with OA, whereas osteoprotegerin (OPG) was higher in OP group. This difference in BAP expression proved to be insignificant after the administration of leptin. Although leptin upregulated the expression of OPG, a significant difference still existed between OA and OP. In conclusion, differential osteogenic potential and responsiveness to leptin of MSCs were noted between postmenopausal women with OA and OP. Differential biological behavior of MSCs seems to be partly related to the different distribution of bone mass between OA and OP populations.

Topics: Adipogenesis; Aged; Aged, 80 and over; Alkaline Phosphatase; Calcification, Physiologic; Cell Differentiation; Cells, Cultured; Collagen Type I; Female; Hip Fractures; Humans; Leptin; Lipoprotein Lipase; Mesenchymal Stem Cells; Osteoarthritis; Osteogenesis; Osteoporosis; Postmenopause; PPAR gamma

Mechanotransduction is the mechanism that due to reacting chondrocytes on biomechanical loading of body mass. Higher biomechanical loading lead to increased degeneration of chondrocytes, whereas moderate loading is protecting. This suggests that body fat regulates bone metabolism first by means of hormonal factors and second that the effects of muscle and loading are signaling factors in mechanotransduction. Leptin, a peptide hormone produced predominantly by white fat cells, is one of these hormonal factors. The aim of this study was to investigate and measure the different effects of weight-bearing on trabecular bone formation in mice without the stimulation of leptin and with or without osteoarthritis.. 40 C57BL/ 6J ob/ob-mice in the age of 20 weeks have been devided into two groups with an ad-libitum-diet and with reduced diet. The hip- and knee-joints have been examinated in micro-CT-scan and histomorphologically.. Animals with an ad-libitum-diet were found to increase body weight significantly at the age of six weeks in comparison with lean mice. At the age of twenty weeks the obese mice were almost twice as heavy as the lean mice. Significant statistical differences are shown between the two groups for body weight and bone mineral density. Examination of trabecular bone in micro-CT revealed that the only statistically significant difference between the two groups was the trabecular number for the proximal femur. High weight-bearing insignificantly improved all trabecular bone parameters in the obese mice. Correlation was found between trabecular number and bone mineral density on the one hand and body weight on the other hand. The correlation between body weight and osteoarthritis shows a significant increase in grade of osteoarthritis as body weight increases in hip-joint and knee-joint but not in osteoarthritis-positive (OP) versus osteoarthritis-negative (ON) mices. The correlation of the hip-joint between micro-CT data and body weight shows an increase in these data as body weight increases in OP mices. The correlation of the hip-joint between micro-CT data and osteoarthritis shows a decrease in these data as osteoarthritis increases in OP mices. The correlation of the knee-joint between micro-CT data and body weight shows differencies between ON and OP mices. The correlation of the knee-joint between micro-CT data and osteoarthritis shows an increase in these data as osteoarthritis increases in OP mices.. biomechanical loading led to decreased bone mineral density by a decrease in the number of trabeculae. Trabecular thickness was not increased by biomechanical loading in growing mice. Decreased body weight in leptin-deficient mice protects against bone loss. This finding is consistent with the principle of light-weight construction of bone. Differences in osteoarthritis-positive and osteoarthritis-negative mices show the eventual importance of diet in leptin-deficience. It is not possible to conclude that these results also apply to human beings.

Topics: Animals; Biomechanical Phenomena; Body Weight; Bone Density; Femur; Hindlimb; Hip Joint; Leptin; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Osteoarthritis; Stress, Mechanical; Tibia; Tomography, X-Ray Computed; Weight-Bearing

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO, PGE(2), IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH(2)-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, and PGE(2), and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE(2) production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.

Topics: Aged; Aged, 80 and over; Cartilage; Dinoprostone; Humans; Inflammation; Interleukin-6; Interleukin-8; JNK Mitogen-Activated Protein Kinases; Leptin; MAP Kinase Signaling System; Middle Aged; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Osteoarthritis

To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology.. Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry.. Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis.. Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.

Topics: Adiposity; Animals; Biomechanical Phenomena; Body Composition; Bone and Bones; Bone Density; Cytokines; Disease Models, Animal; Female; Inflammation; Joints; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity, Morbid; Osteoarthritis; Receptors, Leptin; Risk Factors; Signal Transduction

Topics: Animals; Biomechanical Phenomena; Disease Models, Animal; Humans; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Osteoarthritis; Osteoarthritis, Knee; Receptors, Leptin; Risk Factors

Obesity is one of the most significant, and potentially most preventable, risk factors for the development of osteoarthritis, and numerous studies have shown a strong association between body mass index and osteoarthritis of the hip, knee, foot and hand. However, the mechanism(s) by which obesity contributes to the onset and progression of osteoarthritis are not fully understood. The strong association between body mass index, altered limb alignment, and osteoarthritis of the knee--and the protective effects of weight loss--support the classic hypothesis that the effects of obesity on the joint are due to increased biomechanical loading and associated alterations in gait. However, obesity is now considered to be a low-grade systemic inflammatory disease, and recent studies suggest that metabolic factors associated with obesity alter systemic levels of pro-inflammatory cytokines that are also associated with osteoarthritis. Thus, the ultimate influence of obesity on osteoarthritis may involve a complex interaction of genetic, metabolic, and biomechanical factors. In this respect, mouse models of obesity can provide excellent systems in which to examine causal relationships among these factors. In recent years, there have been surprisingly few reports examining the effects of obesity on osteoarthritis using mouse models. In this paper, we review studies on mice and other animal models that provide both direct and indirect evidence on the role of obesity and altered diet in the development of osteoarthritis. We also examine the use of different body mass indices for characterizing "obesity" in mice by comparing these indices to typical adiposity levels observed in obese humans. Taken together, evidence from studies using mice suggest that a complex interaction of environmental and genetic factors associated with obesity contribute to the incidence and severity of osteoarthritis. The ability to control these factors, together with the development of methods to conduct more intricate measures of local biomechanical factors, make mouse models an excellent system to study obesity and osteoarthritis.

Topics: Adipokines; Adiposity; Animals; Body Composition; Body Mass Index; Disease Models, Animal; Guinea Pigs; Inflammation; Leptin; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis; Osteoarthritis, Hip; Osteoarthritis, Knee; Risk Factors

Topics: Adipokines; Adiponectin; Cartilage, Articular; Female; Homeostasis; Humans; Leptin; Male; Obesity; Osteoarthritis

Adipocytokines are hormone and cytokine like substances produced mainly from white adipose tissue. A relation between plasma adipocytokines and many inflammatory disorders including rheumatoid arthritis (RA) had been investigated. This work was done to investigate the systemic behavior of the main adipocytokines at the plasma level as well as its local behavior at the synovial fluid level in patients with RA and osteoarthritis (OA). The study had been conducted on 32 patients with RA and 18 patients with OA. Paired blood and synovial fluid samples had been collected from all patients and level of plasma and synovial fluid (SF) leptin, adiponectin and resistin had been quantitated by enzyme linked immunosorbent assay (ELISA). Results had been compared between RA group and OA group. Adipocytokines had also been compared in patients with erosive and non-erosive disease and had been related to clinical and laboratory markers of activity. Plasma resistin and BMI-corrected plasma leptin were significantly higher in RA group. Female patients showed significantly higher plasma leptin, even after correction to BMI. Studied SF adipocytokines were significantly higher in RA group and correlated positively with synovial fluid WBCs. Comparing plasma and SF results showed a significant increase in SF resistin especially in RA group and a significant drop of SF adiponectin especially in OA group. In conclusion, Adipocytokines are probably involved in inflammatory and degenerative articular disease. The different behavior between plasma and SF would suggest a pro-inflammatory role for resistin and chondro-protective role for adiponectin.

Topics: Adipokines; Adiponectin; Adult; Arthritis, Rheumatoid; Blood Sedimentation; Body Mass Index; C-Reactive Protein; Cell Count; Female; Humans; Leptin; Leukocytes; Male; Middle Aged; Osteoarthritis; Resistin; Sex Characteristics; Synovial Fluid

A comparative study of bone metabolism between postmenopausal women with osteoarthritis and osteoporosis showed that differential levels of bone remodeling markers, leptin, free leptin index, and osteoprotegerin might partly contribute to the proposed inverse relationship in bone mass between postmenopausal women with osteoarthritis and osteoporosis.. Osteoarthritis (OA) and osteoporosis (OP) are two common disorders affecting the quality of life in the elderly. The association between OA and OP has always been debated. The objective of this study was to compare bone metabolism between postmenopausal women with OA and OP.. A total of 120 postmenopausal women with OA and OP (n = 60, respectively) were included in this comparative study. Anthropometric parameters and BMD at the spine and the proximal femur were measured. Serum leptin, soluble leptin receptor (sLR), osteoprotegerin (OPG), and bone remodeling markers, including bone-specific alkaline phosphatase (BALP), osteocalcin (OC), deoxypyridinoline cross-links (DPD), and cross-linked N-telopeptides of type I collagen (NTX), were quantified with commercial ELISA or EIA kits. Free leptin index (FLI) was also calculated by the ratio between serum leptin and sLR levels.. Postmenopausal women with OA had higher body weight, body mass index, fat mass, and percentage of fat than those suffered from OP. Compared with the patients in OP group, the patients in OA group had significantly higher BMD values at all sites measured. Higher serum leptin and FLI and lower OPG levels were shown in the OA group (leptin: 31.22 +/- 6.4 versus 26.50 +/- 9.27 ng/ml, p < 0.001; FLI: 3.20 +/- 1.02 versus 2.50 +/- 0.95, p < 0.05; OPG: 4.75 +/- 1.97 versus 6.96 +/- 2.75 pM, p < 0.001), whereas lower serum OC and higher urine DPD were noted in the OP group (OC: 16.45 +/- 8.45 versus 13.06 +/- 6.25 ng/ml, p < 0.05; DPD: 10.83 +/- 7.12 versus 15.29 +/- 6.65 nM BCE/mM Cr, p < 0.001). Serum OPG levels negatively correlated with BMD at all sites assessed. However, no correlation was found between leptin and BMD. Only in the OA group di positive correlations exist between FLI and Z-score at the femoral neck and Ward's triangle region. After stepwise regression analysis, it was found that differential factors were able to predict the variance of BMD at different sites to a certain extent.. Our study suggests that there are significant differences in bone metabolism between postmenopausal women with OA and OP and provides evidence for the inverse relationship between OA and OP. Differential levels of bone remodeling markers, leptin, FLI, and OPG may partly contribute to the proposed inverse relationship. Roles of leptin and its soluble receptor in bone metabolism regulation should be explored further.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Bone and Bones; Bone Density; Female; Humans; Leptin; Middle Aged; Osteoarthritis; Osteocalcin; Osteoporosis; Postmenopause; Reproducibility of Results

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-8 production caused by leptin in both rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). RASF and OASF expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-8 production. Leptin-mediated IL-8 production was attenuated by OBRl receptor antisense oligonucleotide, JAK2 inhibitor or STAT3 small interference RNA (siRNA). Transfection with insulin receptor substrate (IRS)-1 siRNA or dominant-negative mutant of p85 and Akt or pretreatment with phosphatidylinositol 3-kinase inhibitor (Ly294002 and wortmannin), Akt inhibitor, NF-kappaB inhibitor (PDTC) and NF-kappaB inhibitor peptide also inhibited the potentiating action of leptin. Stimulation of RASF with leptin activated IkappaB kinase alpha/beta (IKK alpha/beta), p65 phosphorylation at Ser(276), p65 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Moreover, pretreatment with p300 inhibitor (curcumin) also blocked IL-8 expression. The binding of p65 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 acetylation on the IL-8 promoter was enhanced by leptin, which was inhibited by wortmannin, Akt inhibitor or IRS-1 siRNA. These results suggest that leptin increased IL-8 production in synovial fibroblast via the OBRl/JAK2/STAT3 pathway, as well as the activation of IRS1/PI3K/Akt/NF-kappaB-dependent pathway and the subsequent recruitment of p300.

Topics: Adaptor Proteins, Signal Transducing; Arthritis, Rheumatoid; Binding Sites; Cells, Cultured; Fibroblasts; Gene Expression Regulation; Histones; Humans; Insulin Receptor Substrate Proteins; Interleukin-8; Janus Kinase 2; Leptin; NF-kappa B; Osteoarthritis; p300-CBP Transcription Factors; Phosphatidylinositol 3-Kinases; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Synovial Membrane

To investigate leptin's effect on cartilage metabolism and the pathophysiology of osteoarthritis (OA).. Messenger RNA (mRNA) expression and protein levels of leptin and leptin's receptor isoforms were measured by real-time reverse transcription-PCR and Western blot in osteoarthritic and normal cartilage. Osteoarthritic cartilage samples were obtained from two locations of the knee (n=11) and hip (n=6); from the main defective area (advanced OA) and from adjacent macroscopically and histological intact regions (minimal OA). Paired serum and synovial fluid (SF) leptin levels were measured. The effect of leptin was evaluated on chondrocyte proliferation, IL-1beta (interleukin-1beta), NO and metalloproteinases 9 and 13 (MMP-9, MMP-13) protein expression.. Leptin's and leptin's receptor (Ob-Rb) expression levels were significantly increased in advanced OA cartilage compared to minimal. Leptin was significantly increased in SF than serum samples. Also, leptin had a detrimental effect on chondrocyte proliferation and induced IL-1beta production and MMP-9 and MMP-13 protein expression. Furthermore, leptin's mRNA expression in advanced OA cartilage was significantly correlated with BMI of the patients.. The increased leptin levels in SF point toward a local effect of leptin in articular cartilage, while the observed intrajoint differences of leptin and Ob-Rb mRNA expression may be related to the grade of cartilage destruction. The observed production of IL-1beta, MMP-9 and MMP-13 by chondrocytes after leptin treatment indicates a pro-inflammatory and catabolic role of leptin on cartilage metabolism. Furthermore, the observed correlation of leptin's mRNA expression with BMI suggests that leptin may be a metabolic link between obesity and OA.

Topics: Adult; Aged; Aged, 80 and over; Cartilage, Articular; Cell Division; Cells, Cultured; Chondrocytes; Energy Metabolism; Female; Humans; Interleukin-1; Interleukin-1beta; Isomerism; Leptin; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Middle Aged; Nitric Oxide; Obesity; Osteoarthritis; Receptors, Leptin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index

Leptin is a peptide hormone that has an essential role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. The role of leptin in the modulation of the immune response and inflammation has been regarded as important. In rheumatoid arthritis (RA) patients it was reported that fasting leads to an improvement of clinical and biological measures of disease activity, which was associated with a marked decrease in serum leptin. These features suggest that leptin may also influence the inflammatory mechanisms of arthritis in humans. In this study we assessed serum leptin levels in RA and osteoarthritis (OA) patients and found a correlation between serum leptin level and other markers as well as bone mass density changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA and 30 OA patients who constituted the control group. Serum leptin level was determined using the DRG Leptin ELISA Kit-a solid phase enzyme-linked immunosorbent assay based on the sandwich principle. The serum level of leptin in RA patients ranged from 1.8 to 81.1 ng/ml and median value was 11.2. There was a positive correlation between body mass index (BMI) of RA patients and serum level of leptin (correlation coefficients Spearman's r = 0.81). According to correlation coefficients, serum leptin level is independent of age of RA patients, stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration as well as value of titre of the Waaler-Rose, disease activity score (DAS 28) value and presence of rheumatoid nodules. There was a negative correlation between serum leptin level and glomerular filtration rate (GFR). No correlation between the serum leptin level and T-score was found. An influence of steroid treatment on the serum leptin level was not shown. The median serum leptin level in OA patients was 9.2 ng/ml. There was a positive correlation between body mass index of OA patients and serum level of leptin (correlation coefficients Spearman's r = 0.57). No correlation was found between serum leptin level and patient's age, duration of disease and value of laboratory data. There were no correlations between serum leptin level and visual analogue pain scale (VAS) for the lower-limb afflicted patients as well as stage of disease according to Kellgren and Lawrence's score in OA patients. There was a negative correlation between serum leptin level and T-score valu

Topics: Adult; Age Factors; Aged; Arthritis, Rheumatoid; Body Mass Index; Case-Control Studies; Cohort Studies; Female; Humans; Leptin; Male; Middle Aged; Osteoarthritis; Severity of Illness Index; Statistics as Topic

To investigate whether epigenetic mechanisms can regulate leptin's expression and affect its downstream targets as metalloproteinases 3,9,13 in osteoarthritic chondrocytes.. DNA methylation in leptin promoter was measured by DNA bisulfite sequencing, and mRNA expression levels were measured by real-time quantitative PCR in osteoarthritic as well as in normal cartilage. Osteoarthritic articular cartilage samples were obtained from two distinct locations of the knee (n = 15); from the main defective area of maximum load (advanced osteoarthritis (OA)) and from adjacent macroscopically intact regions (minimal OA). Using small interference RNA, we tested if leptin downregulation would affect matrix metalloproteinase (MMP)-13 activity. We also evaluated the effect of the demethylating agent, 5'-Aza-2-deoxycytidine (AZA) and of the histone deacetylase inhibitor trichostatin A (TSA) on leptin expression in chondrocyte cultures. Furthermore, we performed chromatin immunoprecipitation in leptin's promoter area.. We found a correlation between leptin expression and DNA methylation and also that leptin controls MMP-13 activity in chondrocytes. Leptin's downregulation with small interference RNA inhibited MMP-13 expression dramatically. After 5-AZA application in normal chondrocytes, leptin's methylation was decreased, while its expression was upregulated, and MMP-13 was activated. Furthermore, TSA application in normal chondrocyte cultures increased leptin's expression. Also, chromatin immunoprecipitation in leptin's promoter after TSA treatment revealed that histone H3 lysines 9 and 14 were acetylated.. We found that epigenetic mechanisms regulate leptin's expression in chondrocytes affecting its downstream target MMP-13. Small interference RNA against leptin deactivated directly MMP-13, which was upregulated after leptin's epigenetic reactivation, raising the issue of leptin's therapeutic potential for osteoarthritis.

Topics: Acetylation; Adult; Aged; Aged, 80 and over; Analysis of Variance; Azacitidine; Blotting, Western; Cartilage, Articular; Case-Control Studies; Chondrocytes; Decitabine; DNA Methylation; DNA Modification Methylases; Female; Gene Expression; Gene Expression Regulation; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Knee Joint; Leptin; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Middle Aged; Osteoarthritis; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering

Topics: Animals; Cartilage; Homeostasis; Humans; Leptin; Osteoarthritis

In addition to aging, obesity is one of the most common underlying causes of osteoarthritis (OA). Mechanical loading, together with biochemical and systemic factors linked to altered lipid metabolism, are thought to contribute to the onset of OA. It has been suggested that OA is a systemic metabolic disease associated with lipid disorders affecting joint homeostasis. These gradual changes may be due to the local effect of adipokines, and especially leptin. Indeed, their relative levels in joints differ from that found in plasma. In particular, leptin levels are increased and adiponectin and resistin levels are reduced This hypothesis is supported by--leptin overexpression in OA cartilage and its correlation with the degree of cartilage destruction,--abundant leptin synthesis by osteophytes, and--the high leptin levels found in OA joints from female patients. This link between OA and adipokines provides new leads regarding the prevention of OA and the identification of new drug targets.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Age Factors; Aged; Animals; Cartilage, Articular; Chondrocytes; Data Interpretation, Statistical; Disease Models, Animal; Female; Humans; Leptin; Male; Obesity; Osteoarthritis; Osteoarthritis, Knee; Rats; Rats, Wistar; Research; Resistin; Sex Factors; Synovial Fluid; Synovial Membrane

The contribution of leptin, as a possible link between osteoarthritis (OA) and obesity, was studied in cartilage and synovial fluid samples obtained from osteoarthritic patients. Its effect on cartilage was evaluated in rats after intraarticular injections of leptin. Leptin levels were measured in the synovial fluid samples by enzyme linked immunosorbent assay; leptin concentrations were correlated with the body mass index. Leptin was strongly expressed in osteophytes and OA cartilage, while, in normal cartilage, few chondrocytes produced leptin. The level of leptin expression was related to the grade of cartilage destruction and was in good relation with those of growth factors as IGF1 and TGFb. Studies in rats showed that intraarticular leptin injection stimulated anabolic functions of chondrocytes and induced the synthesis of leptin, IGF1 and TGFB in cartilage at both the chondrocytes and induced the synthesis of leptin, IGF1 and TGFB in cartilage at both the mRNA and protein levels. In conclusion, leptin may be a link between osteoarthritis and obesity, and may play a key role in cartilage metabolism. Leptin may contribute to the pathophysiology of OA.

Topics: Animals; Bone and Bones; Cartilage; Immunologic Factors; Leptin; Obesity; Osteoarthritis; Osteoblasts; Rats; Synovial Fluid

To evaluate the contribution of leptin (an adipose tissue-derived hormone) to the pathophysiology of osteoarthritis (OA), by determining the level of leptin in both synovial fluid (SF) and cartilage specimens obtained from human joints. We also investigated the effect of leptin on cartilage, using intraarticular injections of leptin in rats.. Leptin levels in SF samples obtained from OA patients undergoing either knee replacement surgery or knee arthroscopy were measured by enzyme-linked immunosorbent assay. In addition, histologic sections of articular cartilage and osteophytes obtained during surgery for total knee replacement were graded using the Mankin score, and were immunostained using antibodies to leptin, transforming growth factor beta (TGFbeta), and insulin-like growth factor 1 (IGF-1). For experimental studies, various doses of leptin (10, 30, 100, and 300 microg) were injected into the knee joints of rats. Tibial plateaus were collected and processed for proteoglycan synthesis by radiolabeled sulfate incorporation, and for expression of leptin, its receptor (Ob-Rb), and growth factors by reverse transcriptase-polymerase chain reaction and immunohistochemical analysis.. Leptin was observed in SF obtained from human OA-affected joints, and leptin concentrations correlated with the body mass index. Marked expression of the protein was observed in OA cartilage and in osteophytes, while in normal cartilage, few chondrocytes produced leptin. Furthermore, the pattern and level of leptin expression were related to the grade of cartilage destruction and paralleled those of growth factors (IGF-1 and TGFbeta1). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF-1 and TGFbeta1 in cartilage at both the messenger RNA and the protein levels.. These findings suggest a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicate that leptin may play an important role in the pathophysiology of OA.

Topics: Aged; Aged, 80 and over; Animals; Cartilage, Articular; Dose-Response Relationship, Drug; Female; Humans; Immunohistochemistry; Injections, Intra-Articular; Insulin-Like Growth Factor I; Knee Joint; Leptin; Male; Middle Aged; Osteoarthritis; Rats; Rats, Wistar; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Synovial Fluid; Tibia; Transforming Growth Factor beta; Transforming Growth Factor beta1