osteoprotegerin and Chronic-Disease

Periodontal and periapical lesions are infectious inflammatory osteolitytic conditions in which a complex inflammatory immune response mediates bone destruction. However, the uncertainty of a lesion's progressive or stable phenotype complicates understanding of the cellular and molecular mechanisms triggering lesion activity. Evidence from clinical and preclinical studies of both periodontal and periapical lesions points to a high receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio as the primary determinant of osteolytic activity, while a low RANKL/OPG ratio is often observed in inactive lesions. Proinflammatory cytokines directly modulate RANKL/OPG expression and consequently drive lesion progression, along with pro-osteoclastogenic support provided by Th1, Th17, and B cells. Conversely, the cooperative action between Th2 and Tregs subsets creates an anti-inflammatory and proreparative milieu associated with lesion stability. Interestingly, the trigger for lesion status switch from active to inactive can originate from an unanticipated RANKL immunoregulatory feedback, involving the induction of Tregs and a host response outcome with immunological tolerance features. In this context, dendritic cells (DCs) appear as potential determinants of host response switch, since RANKL imprint a tolerogenic phenotype in DCs, described to be involved in both Tregs and immunological tolerance generation. The tolerance state systemically and locally suppresses the development of exacerbated and pathogenic responses and contributes to lesions stability. However, immunological tolerance break by comorbidities or dysbiosis could explain lesions relapse toward activity. Therefore, this article will provide a critical review of the current knowledge concerning periodontal and periapical lesions activity and the underlying molecular mechanisms associated with the host response. Further studies are required to unravel the role of immunological responsiveness or tolerance in the determination of lesion status, as well as the potential cooperative and/or inhibitory interplay among effector cells and their impact on RANKL/OPG balance and lesion outcome.

Topics: Chronic Disease; Cytokines; Humans; Osteoprotegerin; RANK Ligand; Th17 Cells

The mortality of end-stage renal disease (ESRD) patients, including those receiving long-term peritoneal dialysis (PD), has remained unacceptably high owing to the prevalence of cardiovascular disease. It is well recognized that both traditional Framingham risk factors and kidney disease-related risk factors may contribute to the high prevalence of cardiovascular disease in these patients. Of the different risk factors, chronic inflammation frequently is observed in long-term PD patients. The causes of inflammation are usually complex and multifactorial, involving both dialysis-related and dialysis-unrelated factors. Inflammation is strongly associated with cardiovascular disease and malnutrition, and has been shown consistently to be a powerful predictor of mortality and adverse cardiovascular outcomes in PD patients. In this article we review the prevalence and potential causes of chronic inflammation in PD patients. More importantly, we provide emerging evidence that shows the serious consequences of chronic systemic inflammation in PD patients and the important contribution of inflammation to adverse clinical outcomes.

Topics: C-Reactive Protein; Cachexia; Calcinosis; Cardiomegaly; Chronic Disease; Heart Failure; Humans; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Osteoprotegerin; Peritoneal Dialysis; Prevalence

The mortality rate is extremely high in chronic kidney disease (CKD), primarily due to the high prevalence of cardiovascular disease (CVD) in this patient group. Apart from traditional Framingham risk factors, evidences suggest that nontraditional risk factors, such as inflammation, oxidative stress, endothelial dysfunction, and vascular calcification also contribute to this extremely high risk of CVD. Disturbance in the mineral metabolism, especially in the ions of Ca and PO4, are linked to enhanced calcification of blood vessels. Although the mechanism(s) of this enhanced calcification process are not fully understood, current knowledge suggests that a large number (and an imbalance between them) of circulating promoters and inhibitors of the calcification process, that is, fetuin-A (or alpha 2-Heremans-Schmid glycoprotein, AHSG), matrix-Gla protein (MGP), osteoprotegerin (OPG), osteopontin (OPN), bone morphogenetic proteins (BMPs), and inorganic pyrophosphate (PPi), are involved in the deterioration of vascular tissue. Thus, an imbalance in these factors may contribute to the high prevalence of vascular complications in CKD patients. Among these mediators, studies on fetuin-A deserve further attention as clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification, all-cause and cardiovascular mortality in CKD patients. Both chronic inflammation and the uremic milieu per se may contribute to fetuin-A depletion, as well as specific mutations in the AHSG gene. Recent experimental and clinical studies also suggest an intriguing link between fetuin-A, insulin resistance, and the metabolic syndrome.

Topics: alpha-2-HS-Glycoprotein; Blood Proteins; Bone Morphogenetic Protein 7; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Chronic Disease; Extracellular Matrix Proteins; Humans; Inflammation; Kidney Diseases; Matrix Gla Protein; Metabolic Syndrome; Osteopontin; Osteoprotegerin; Vascular Diseases

Rheumatoid arthritis is characterized by the presence of inflammatory synovitis and destruction of joint cartilage and bone. Tissue proteinases released by synovia, chondrocytes and pannus can cause cartilage destruction and cytokine-activated osteoclasts have been implicated in bone erosions. Rheumatoid arthritis synovial tissues produce a variety of cytokines and growth factors that induce monocyte differentiation to osteoclasts and their proliferation, activation and longer survival in tissues. More recently, a major role in bone erosion has been attributed to the receptor activator of nuclear factor kappa B ligand (RANKL) released by activated lymphocytes and osteoblasts. In fact, osteoclasts are markedly activated after RANKL binding to the cognate RANK expressed on the surface of these cells. RANKL expression can be upregulated by bone-resorbing factors such as glucocorticoids, vitamin D3, interleukin 1 (IL-1), IL-6, IL-11, IL-17, tumor necrosis factor-alpha, prostaglandin E2, or parathyroid hormone-related peptide. Supporting this idea, inhibition of RANKL by osteoprotegerin, a natural soluble RANKL receptor, prevents bone loss in experimental models. Tumor growth factor-beta released from bone during active bone resorption has been suggested as one feedback mechanism for upregulating osteoprotegerin and estrogen can increase its production on osteoblasts. Modulation of these systems provides the opportunity to inhibit bone loss and deformity in chronic arthritis.

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Bone Resorption; Carrier Proteins; Chronic Disease; Cytokines; Disease Models, Animal; Glycoproteins; Humans; Membrane Glycoproteins; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Our aim was to explore potential use of temporal profiles of seven emerging cardio-renal and two pulmonary candidate biomarkers for predicting future adverse clinical outcome in stable patients with chronic heart failure (CHF).. In 263 CHF patients, we determined the risk of a composite endpoint of HF-hospitalization, cardiac death, LVAD-placement and heart transplantation in relation to repeatedly assessed (567 samples in total) blood biomarker levels, and slopes of their temporal trajectories (i.e., rate of biomarker change per year). In each patient, we estimated biomarker trajectories using repeatedly measured osteopontin (OPN), osteoprotegerin (OPG), epidermal growth factor receptor (EGFR), heparin-binding protein (HBP), trefoil factor-3 (TFF3), kallikrein-6 (KLK-6), matrix extracellular phosphoglycoprotein (MEPE), pulmonary surfactant-associated protein-D (PSP-D), and secretoglobulin family 3A-member-2 (SCGB3A2).. During 2.2 years of follow-up, OPN, OPG, and HBP levels predicted the composite endpoint (univariable hazard ratio [95% confidence interval] per 1SD increase: 2.31 [1.76-3.15], 2.23 [1.69-3.00], and 1.36[1.09-1.70]). Independently of the biomarkers' levels, the slopes of OPG, TFF-3, PSP-D trajectories were also strong clinical predictors (per 0.1SD increase: 1.24 [1.14-1.38], 1.31 [1.17-1.49], and 1.32 [1.21-1.47]). All associations persisted after multivariable adjustment for baseline characteristics, and repeatedly assessed CHF pharmacological treatment and cardiac biomarkers NT-proBNP and troponin T.. Repeatedly-measured levels of OPN, OPG, and HBP, and slopes of OPG, TFF-3, and PSP-D strongly predict clinical outcome. These candidate biomarkers may be clinically relevant as they could further define a patient's risk and provide additional pathophysiological insights into CHF.

Topics: Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Cohort Studies; ErbB Receptors; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Kidney; Lung; Male; Middle Aged; Natriuretic Peptide, Brain; Netherlands; Osteoprotegerin; Peptide Fragments; Prospective Studies; Time Factors

The aim of this study was to evaluate the association between genetic polymorphisms and the comorbid presence of chronic systemic arthralgia in patients with articular temporomandibular disorders (TMD). Subjects were evaluated for the presence of TMD and asked about the presence of chronic joint pain. Four groups were included in the study: articular TMD and systemic arthralgia (n=85), no articular TMD and systemic arthralgia (n=82), articular TMD and no systemic arthralgia (n=21), no articular TMD and no systemic arthralgia (control, n=72). A total of 14 single nucleotide polymorphisms in the OPG, RANK, and RANKL genes were investigated. In the statistical analysis, a P-value of <0.05 was considered significant. For the OPG gene, an association was observed between the group with chronic arthralgia and joint TMD and the control group (P=0.04). There was also a tendency towards an association of the haplotype CGCCAA with an increased risk of developing chronic joint pain, even in the absence of TMD (P=0.06). For the RANK gene, the AGTGC haplotype was associated with the lowest risk of presenting chronic joint pain in individuals without TMD (P=0.03). This study supports the hypothesis that changes in the OPG and RANK genes influence the presence of chronic joint pain in individuals with and without TMD.

Topics: Adolescent; Adult; Aged; Arthralgia; Chronic Disease; Comorbidity; Cross-Sectional Studies; Female; Genotype; Haplotypes; Humans; Linkage Disequilibrium; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Temporomandibular Joint Disorders

Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF), and circulating levels predict survival in patients with postinfarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy.. OPG as a risk factor for the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329), and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥60 years, New York Heart Association class II to IV, ischemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multivariate analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary end point (adjusting for left ventricular ejection fraction, New York Heart Association class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1, and N-terminal pro-B-type natriuretic peptide). However, OPG added independent predictive information for WHF hospitalization (hazard ratio [HR] 1.10 [1.04 to 1.16], P<0.001) and all-cause mortality/WHF hospitalization (HR 1.06 [1.01 to 1.11]). The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (tertile 1, HR=0.66 unadjusted [P=0.025]; HR=0.71 Cox adjusted [P=0.025]; interaction by treatment effect for the tertiles P=0.086).. OPG added no predictive information for the primary end point, but independently predicted WHF hospitalization in older patients with advanced chronic systolic HF of ischemic etiology. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00206310.

Topics: Aged; Aged, 80 and over; Biomarkers; Chronic Disease; Europe; Female; Fluorobenzenes; Heart Failure; Hospitalization; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Lipids; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Proportional Hazards Models; Pyrimidines; Risk Assessment; Risk Factors; Rosuvastatin Calcium; Sulfonamides; Time Factors; Treatment Outcome

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Topics: Chronic Disease; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with an increased prevalence of subclinical atherosclerosis and cardiovascular risk. Angiopoietin-2 (Ang-2), asymmetric dimethylarginine (ADMA), and osteoprotegerin (OPG) are molecules related to endothelial dysfunction (ED) and atherosclerosis, but also to disease severity in patients with chronic inflammatory disorders. In this case-control study, we aimed to investigate serum Ang-2, ADMA, and OPG levels in patients with HS, and to assess the potential relationship between these levels and disease severity. Seventy-five patients with HS and 60 controls were assessed. Serum Ang-2, ADMA, and OPG concentrations were determined in all participants. HS patients had significantly higher Ang-2 and ADMA levels than controls after adjusting for confounders. Besides, Ang-2 concentrations positively correlated with disease severity in the adjusted multivariable analysis. Nevertheless, serum OPG levels did not significantly differ between HS patients and controls. Our results indicate that serum Ang-2 and ADMA levels are significantly increased in patients with HS. Furthermore, Ang-2 might be a suitable marker of HS severity.

Topics: Angiopoietin-2; Arginine; Atherosclerosis; Biomarkers; Case-Control Studies; Chronic Disease; Hidradenitis Suppurativa; Humans; Osteoprotegerin

Plasma osteoprotegerin (OPG) and vascular smooth muscle cell (VSMC) derived extracellular vesicles (EVs) are important regulators in the process of vascular calcification (VC). In population studies, high levels of OPG are associated with events. In animal studies, however, high OPG levels result in reduction of VC. VSMC-derived EVs are assumed to be responsible for OPG transport and VC but this role has not been studied. For this, we investigated the association between OPG in plasma and circulating EVs with coronary artery calcium (CAC) as surrogate for VC in symptomatic patients. We retrospectively assessed 742 patients undergoing myocardial perfusion imaging (MPI). CAC scores were determined on the MPI-CT images using a previously developed automated algorithm. Levels of OPG were quantified in plasma and two EV-subpopulations (LDL and TEX), using an electrochemiluminescence immunoassay. Circulating levels of OPG were independently associated with CAC scores in plasma; OR 1.39 (95% CI 1.17-1.65), and both EV populations; EV-LDL; OR 1.51 (95% CI 1.27-1.80) and EV-TEX; OR 1.21 (95% CI 1.02-1.42). High levels of OPG in plasma were independently associated with CAC scores in this symptomatic patient cohort. High levels of EV-derived OPG showed the same positive association with CAC scores, suggesting that EV-derived OPG mirrors the same pathophysiological process as plasma OPG.

Topics: Aged; Biomarkers; Chronic Disease; Coronary Artery Disease; Coronary Vessels; Extracellular Vesicles; Female; Humans; Male; Middle Aged; Myocardial Perfusion Imaging; Osteoprotegerin; Prospective Studies; Retrospective Studies; Risk Assessment; Risk Factors; Syndrome; Vascular Calcification

Evidence of osteitis is frequently observed in patients with chronic rhinosinusitis (CRS), especially in recalcitrant cases. However, studies focusing on biological markers of osteitis are limited and it remains unclear whether osteitis is associated with different phenotypes of CRS. This study aimed to analyze the expression and assess the roles of receptor activator of nuclear factor κB ligand (RANKL) in patients with CRS and osteitis.. CRS patients with nasal polyps (CRSwNP, n = 63), CRS patients without nasal polyps (CRSsNP, n = 8), and control subjects (n = 12) were enrolled. Histologic phenotypes, clinical information, and computed tomography (CT) scores were investigated. The Global Osteitis Scoring Scale (GOSS) and RANKL, a molecular marker of bone remodeling, were analyzed in each type of CRS. CRS mouse models were treated with anti-RANKL.. GOSS values were significantly higher in all CRS patients than in the control group. The GOSS value in non-eosinophilic CRSwNP was higher than in eosinophilic CRSwNP. RANKL was upregulated whereas decoy receptor osteoprotegerin (OPG) was downregulated in CRS. RANKL messenger RNA (mRNA) and protein levels were positively correlated with GOSS. RANKL/OPG was increased in recurrent cases compared with primary cases. Multiple inflammatory mediators were positively correlated with the protein level of RANKL in CRS tissues. In the mouse CRSwNP model, anti-RANKL treatment abrogated mucosal inflammation and bone remodeling.. RANKL expression is associated with clinical osteitis and disease severity in CRSwNP. These findings shed light on the importance of RANKL as a potential biomarker of CRS and a key player in CRS pathogenesis.

Topics: Adult; Animals; Biomarkers; Chronic Disease; Cytokines; Disease Models, Animal; Eosinophilia; Female; Humans; Male; Mice; Middle Aged; Nasal Polyps; Osteitis; Osteoprotegerin; RANK Ligand; Rhinitis; Sinusitis

Chronic otitis media (COM) is an important debilitating public problem causing hearing loss due to irreversible resorption of the ossicular chain. Activation of osteoprotegerin (OPG) during an acute attack of COM prevents bone resorption.The aim of the study was to investigate the role of OPG gene expression level on ossicular chain resorption in chronic otitis media.. Fifty operated COM patients were included in the study. While 20 patients underwent ossiculoplasty, 30 patients underwent type 1 tympanoplasty. For RNA isolation and OPG gene expression analysis, middle ear swabs were taken from nasopharynx in the ostium of the Eustachian tube. RNA was isolated with mRNA easy kit and kept at - 85 °C till the cDNA and expression analysis. Expression levels were analyzed with real-time quantitative PCR in comparison with PDGB gene expression level as an internal control.. Sample Cq measurements of type 1 tympanoplasty group were higher than Cq measurements of the internal control group (p = 0.027; p < 0.05). In contrast, there was no statistically significant difference between sample Cq measurements of ossiculoplasty group and Cq measurements of the internal control group (p = 0.293; p > 0.05).. Since OPG gene expression level was significantly higher in type 1 tympanoplasty group, OPG gene regulation system may have an effect on ossicular chain destruction in COM.

Topics: Adolescent; Adult; Bone Resorption; Chronic Disease; Ear Ossicles; Eustachian Tube; Female; Gene Expression; Humans; Male; Middle Aged; Ossicular Prosthesis; Osteoprotegerin; Otitis Media; Tympanoplasty; Young Adult

Topics: Acute Disease; Adult; Bone Remodeling; Chronic Disease; Female; Hemorrhage; Humans; Male; Middle Aged; Osteoprotegerin; Periodontitis; RANK Ligand; Saliva; Up-Regulation; Young Adult

Topics: Adult; Biomarkers; Case-Control Studies; Chronic Disease; Female; Follow-Up Studies; Gene Expression Regulation; Humans; Interleukin-33; Male; Middle Aged; Osteoprotegerin; Periapical Periodontitis; Prognosis; RANK Ligand

Hepatic osteodystrophy is multifactorial in its pathogenesis. Numerous studies have shown that impairments of the hepatic growth hormone/insulin-like growth factor-1 axis (GH/IGF-1) are common in patients with non-alcoholic fatty liver disease, chronic viral hepatitis, liver cirrhosis, and chronic cholestatic liver disease. Moreover, these conditions are also associated with low bone mineral density (BMD) and greater fracture risk, particularly in cortical bone sites. Hence, we addressed whether disruptions in the GH/IGF-1 axis were causally related to the low bone mass in states of chronic liver disease using a mouse model of liver-specific GH-receptor (GHR) gene deletion (Li-GHRKO). These mice exhibit chronic hepatic steatosis, local inflammation, and reduced BMD. We then employed a crossing strategy to restore liver production of IGF-1 via hepatic IGF-1 transgene (HIT). The resultant Li-GHRKO-HIT mouse model allowed us to dissect the roles of liver-derived IGF-1 in the pathogenesis of osteodystrophy during liver disease. We found that hepatic IGF-1 restored cortical bone acquisition, microarchitecture, and mechanical properties during growth in Li-GHRKO-HIT mice, which was maintained during aging. However, trabecular bone volume was not restored in the Li-GHRKO-HIT mice. We found increased bone resorption indices in vivo as well as increased basal reactive oxygen species and increased mitochondrial stress in osteoblast cultures from Li-GHRKO and the Li-GHRKO-HIT compared with control mice. Changes in systemic markers such as inflammatory cytokines, osteoprotegerin, osteopontin, parathyroid hormone, osteocalcin, or carboxy-terminal collagen cross-links could not fully account for the diminished trabecular bone in the Li-GHRKO-HIT mice. Thus, the reduced serum IGF-1 associated with hepatic osteodystrophy is a main determinant of low cortical but not trabecular bone mass. © 2017 American Society for Bone and Mineral Research.

Topics: Animals; Biomechanical Phenomena; Bone Density; Bone Diseases, Metabolic; Cancellous Bone; Chronic Disease; Cortical Bone; Cytokines; Fatty Liver; Inflammation; Inflammation Mediators; Insulin-Like Growth Factor I; Liver; Mice, Inbred C57BL; Mice, Transgenic; Organ Size; Organ Specificity; Osteoblasts; Osteopontin; Osteoprotegerin; Receptors, Somatotropin; Transgenes; X-Ray Microtomography

To evaluate the effect of anti-TNF treatments on bone mineral density (BMD), bone remodelling markers (BRM) and receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) in patients with chronic inflammatory joint diseases.. A longitudinal prospective study was performed under clinical practice conditions on 31 patients diagnosed of rheumatoid arthritis, psoriatic arthropathy and ankylosing spondylitis who had received treatment with anti-TNF alpha drugs for one year. BMD, OPG and RANKL soluble form (sRANKL) were studied at the onset and end of the study. During the study (0, 3, 6, 9 and 12 month), disease activity (SDAI, BASDAI and CRP), functional capacity (HAQ, BASFI), BRM and vitamin D were studied.. BMD was not modified after one year of treatment. The patients who took corticosteroids had a mean bone mass loss of 3% in the lumbar spine (±1.6, P=.02). In regards to the BRM, did not experience significant changes over the course of the study. Disease activity, both SDAI (P=.002) and BASDAI (P=.002), decreased. OPG was maintained without changes during the year of treatment while both the sRANKL (0.28±0.22, P=.013) and sRANKL/OPG ratio significantly decreased (0.04±0.03, P=.031).. The patients being treated with anti-TNF did not present with a significant loss of DMO during the study (one year), at the same time experiencing an improvement in disease activity. This protection has been clearer in the responding patients.

Topics: Adalimumab; Adult; Aged; Anti-Inflammatory Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Biomarkers; Bone Density; Bone Remodeling; Chronic Disease; Etanercept; Female; Humans; Infliximab; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Spondylitis, Ankylosing; Treatment Outcome; Tumor Necrosis Factor-alpha

The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis may play an important role in the stabilization of restored sinus rhythm (SR) after mitral valve (MV) surgery by stimulating atrial fibrillation (AF)-related atrial remodeling in AF patients. Herein, we investigated the association between preoperative serum soluble RANKL (sRANKL)/OPG and the stabilization of restored SR after MV surgery.. Persistent AF patients who had spontaneously restored SR after MV replacement were enrolled (n = 203). Comparison was made between patients without AF recurrence (n = 71) and patients experiencing recurrence (n = 132).. Patients experiencing recurrence had higher serum levels of sRANKL, OPG and sRANKL/OPG ratio than patients without recurrence. Multivariate survival regression analysis showed that clinical factors such as duration of AF, left atrial diameter and left atrial thrombosis, as well as serum sRANKL level and the sRANKL/OPG ratio, were independent predictors of AF recurrence. Receiver operating characteristic curve analysis showed that the best diagnostic values of the serum sRANKL level and the sRANKL/OPG ratio for predicting recurrence were 3.44 pmol/l and 0.53, respectively.. Patients who had a low preoperative serum sRANKL level and sRANKL/OPG ratio are likely to have a stable spontaneously restored SR postoperatively. Thus, we suggest that patients at high risk of early AF recurrence should be considered for concomitant surgical cardioversion during MV surgery.

Topics: Atrial Fibrillation; Biomarkers; Chronic Disease; Female; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Stenosis; Osteoprotegerin; Preoperative Care; Receptor Activator of Nuclear Factor-kappa B; Secondary Prevention

Osteoprotegerin (OPG) plays a key role in atherosclerosis progression and plaque destabilization. We investigated the relationship between intima-media thickness of the common carotid artery (CCA-IMT; an early marker of atherosclerosis) and OPG levels in patients with acute coronary syndrome (ACS) and chronic coronary artery disease (CAD).. We studied 133 consecutive patients, mean age 65 ± 9 years, referred to our department for coronary angiography. They were evaluated for cardiovascular risk factors, OPG levels and CCA-IMT and accordingly divided in two subgroups: ACS and chronic CAD.. Except for age, the two groups were similar according to conventional cardiovascular risk factors. The chronic CAD group showed a CCA-IMT lower than the ACS group (0.86 ± 0.15 vs. 0.94 ± 0.22 mm, P = 0.027); there were no differences regarding the extension of coronary atherosclerosis on angiograms. The OPG levels were higher in chronic CAD patients than in ACS patients (5.36 ± 3.06 vs. 3.85 ± 2.96 pmol/l, P = 0.004). Moreover, the CCA-IMT was significantly correlated with the age of the patients (r = 0.5; P < 0.001). OPG values were not related either to age or to the CCA-IMT. At analysis of covariance, when adjusting the groups for age, the comparison of the two groups lost statistical significance for CCA-IMT (P = 0.41), whereas the OPG values remained significant after the correction (P = 0.001).. OPG levels are higher in chronic CAD patients. CCA-IMT confirmed its importance in predicting CAD, showing significantly higher values in the patients in the ACS group as compared with those in the chronic CAD group.

Topics: Acute Coronary Syndrome; Aged; Carotid Intima-Media Thickness; Chronic Disease; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Osteoprotegerin; Risk Factors

Vascular calcification is associated with increased cardiovascular mortality in chronic hemodialysis patients. This prospective study investigated the relationship between serum osteoprotegerin, receptor activator of NF-κB ligand, inflammatory markers, and progression of coronary artery calcification score.. Seventy-eight hemodialysis patients were enrolled. Serum IL-1β, IL-6, TNF-α, osteoprotegerin, receptor activator of NF-κB, fetuin A, and bone alkaline phosphatase were measured by ELISA. Coronary artery calcification score was measured two times with 1-year intervals, and patients were classified as progressive or nonprogressive.. Baseline and first-year serum osteoprotegerin levels were significantly higher in the progressive than nonprogressive group (17.39±9.67 versus 12.90±6.59 pmol/L, P=0.02; 35.17±18.35 versus 24±11.65 pmol/L, P=0.002, respectively). The ratio of serum osteoprotegerin to receptor activator of NF-κB ligand at 1 year was significantly higher in the progressive group (0.26 [0.15-0.46] versus 0.18 [0.12-0.28], P=0.004). Serum osteoprotegerin levels were significantly correlated with coronary artery calcification score at both baseline (r=0.36, P=0.001) and 1 year (r=0.36, P=0.001). Importantly, progression in coronary artery calcification score significantly correlated with change in serum osteoprotegerin levels (r=0.39, P=0.001). In addition, serum receptor activator of NF-κB ligand levels were significantly inversely correlated with coronary artery calcification scores at both baseline (r=-0.29, P=0.01) and 1 year (r=-0.29, P=0.001). In linear regression analysis for predicting coronary artery calcification score progression, only baseline coronary artery calcification score and change in osteoprotegerin were retained as significant factors in the model.. Baseline coronary artery calcification score and serum osteoprotegerin levels were significantly associated with progression of coronary artery calcification score in hemodialysis patients.

Topics: Adult; Aged; Biomarkers; Chi-Square Distribution; Chronic Disease; Coronary Artery Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Inflammation Mediators; Kidney Diseases; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Turkey; Vascular Calcification

Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling.. In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition.. CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk.. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.

Topics: Aged; Animals; Biomarkers; Bone Marrow; Bone Remodeling; Case-Control Studies; Cell Differentiation; Cells, Cultured; Chronic Disease; Cohort Studies; Collagen Type I; Comorbidity; Coronary Artery Disease; Disease Models, Animal; Female; Heart Failure; Humans; Male; Mesenchymal Stem Cells; Mice; Mice, Inbred BALB C; Middle Aged; Osteoclasts; Osteoporosis; Osteoprotegerin; Peptides; RANK Ligand; Regression Analysis

Heart failure (HF) had been reported with increased risk of hip fractures. However, the relationship between circulating biomarkers and bone mineral density (BMD) in chronic HF remained unclear.. This is a cross-sectional study which recruited stable chronic HF from registry of the Heart Failure Center of National Taiwan University Hospital. Patients underwent dual-energy x-ray absorptiometry (DEXA) measurements at hip and lumbar spines and biochemical assessments including B-type natriuretic peptide (BNP-32), myostatin, follistatin and osteoprotegerin (OPG).. A total of 115 stable chronic HF individuals with left ventricular ejection fraction (EF) <45% (74% of male, mean age at 59) were recruited with 24 patients in NYHA class I, 73 patients in NYHA class II and 18 patients in NYHA class III. Results of BMD showed that Z scores of hip in NYHA III group (-0.12 ± 1.15) was significantly lower than who were NYHA II (0.58 ± 1.04). Serum OPG was significantly higher in subjects of NYHA III (9.3 ± 4.6 pmol/l) than NYHA II (7.4 ± 2.8 pmol/l) or NYHA I (6.8 ± 3.6 pmol/l) groups. There's a significant negative association between log transformed serum OPG and trochanteric BMD (R = -0.299, P = 0.001), which remained significant after multivariate analysis.. Our study demonstrated an inverse association between serum OPG and trochanteric BMD in patients with HF. OPG may be a predictor of BMD and an alternative to DEXA for identifying at risk HF patients for osteoporosis.

Topics: Absorptiometry, Photon; Adult; Aged; Biomarkers; Bone Density; Chronic Disease; Cross-Sectional Studies; Female; Femur; Heart Failure; Humans; Lumbar Vertebrae; Male; Middle Aged; Multivariate Analysis; Osteoporosis; Osteoprotegerin

High PTH levels have been reported in patients with chronic heart failure (CHF). Similarly, its levels increase with aging and are related to impaired survival in elderly adults. However, its relationship with neuroendocrine activation and endothelial dysfunction in CHF has not been previously studied. Seventy-three CHF males with New York Heart Association (NYHA) classes II and III and 20 control subjects aged ≥ 55 yr were recruited. PTH, 25-hydroxyvitamin D [25(OH)D], N-terminal pro-brain natriuretic peptide (NT-pro-BNP), adiponectin, and osteoprotegerin were measured. Endothelial function (brachial flow mediated dilation), echocardiography, physical performance, and quality of life were assessed, as well. CHF patients had markedly increased serum PTH (77 ± 33 vs 40 ± 11 pg/ml, p<0.0001), NT-pro-BNP [1809 (2742) vs 67 (74) pg/ml, p<0.0001], adiponectin (17 ± 9 vs 10 ± 2 μg/ml, p<0.0001), osteoprotegerin, whereas 25(OH)D levels were decreased compared to controls. Increased PTH is positively correlated with NTpro- BNP (r=0.399, p<0.0001), adiponectin (r=0.398, p<0.0001), and osteoprotegerin, whereas negatively with 25(OH)D in CHF patients. Additionally, increased serum PTH was associated with endothelial dysfunction, echocardiographic variables of heart failure progression, impaired physical performance, and deteriorated quality of life. In a multivariate linear regression analysis, increased serum PTH was independently associated with neuroendocrine activation (NT-pro-BNP, adiponectin) and endothelial dysfunction in elderly CHF men (R2=0.455). Additionally, demonstrated relations with other well-established variables of heart failure severity suggest the potential role of serum PTH in the pathogenesis and non-invasive monitoring of heart failure progression. Future studies are needed to evaluate the predictive value of serum PTH for clinical outcomes as well as beneficial potential of PTH suppression in CHF patients.

Topics: Adiponectin; Aged; Chronic Disease; Endothelium, Vascular; Heart Failure; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Neurosecretory Systems; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; ROC Curve; Vascular Diseases; Vitamin D

We investigated the risk factors for radiographic bone damage to foot joints in patients with chronic gout among various patient characteristics and serum inflammatory cytokines such as interleukin 1ß (IL-1ß), IL-6, soluble IL-6 receptor (sIL-6R), osteoprotegerin (OPG), and receptor activator of nuclear factor-κB ligand (RANKL).. Fifty consecutive male patients with gout and 54 age-matched healthy male controls were enrolled. Serum levels of cytokines including IL-1ß, IL-6, sIL-6R, OPG, and RANKL were measured using ELISA. Radiographic damage indices including erosion scores, narrowing scores, and total scores for foot joints were assessed according to a modified Sharp-van der Heijde system.. There were significant differences in serum IL-1ß, IL-6, sIL-6R, OPG, and RANKL levels between patients with gout and the controls, after adjustment for confounding factors such as age, body mass index, blood urea nitrogen, creatinine, triglyceride, and fasting blood glucose (p = 0.034 for IL-1ß, p < 0.001 for IL-6, p = 0.040 for sIL-6R, p = 0.002 for OPG, and p = 0.018 for RANKL). Radiographic damage indices (erosion, narrowing, and total scores) were negatively associated with serum sIL-6R and OPG levels in multivariable-adjusted regression analysis. Serum sIL-6R levels in patients without radiographic damage were higher than in those with damage (p = 0.006).. Radiographic damage in patients with chronic gouty arthritis was negatively associated with serum sIL-6R and OPG. Further study on the role of inflammatory cytokines in the pathogenesis of radiographic damage in gout is needed.

Topics: Adult; Bone and Bones; Chronic Disease; Gout; Humans; Interleukin-1beta; Male; Middle Aged; Osteoprotegerin; Radiography; RANK Ligand; Receptors, Interleukin-6

The proteasome inhibitor bortezomib has potent anti-myeloma and bone-protective activity. Recently, bortezomib was shown to directly inhibit osteoclastogenesis. The aim of this study was to analyze the influence and therapeutic effect of bortezomib in a mouse model of inflammatory arthritis.. Heterozygous human tumor necrosis factor α (hTNFα)-transgenic mice and their wild-type (WT) littermates were intravenously injected with 0.75 mg/kg of bortezomib or phosphate buffered saline twice weekly. The mice were assessed for clinical signs of arthritis. After 6 weeks of treatment, mice were analyzed for synovial inflammation, cartilage damage, bone erosions, and systemic bone changes. Osteoclast precursors from WT and hTNF-transgenic mice were isolated from bone marrow, treated with bortezomib, and analyzed for osteoclast differentiation, bone resorption, and expression of osteoclast-specific genes as well as apoptosis and ubiquitination.. Bortezomib-treated hTNF-transgenic mice showed moderately increased inflammatory activity and dramatically enhanced bone erosions associated with a significant increase in the number of synovial osteoclasts. Interestingly, bortezomib did not alter systemic bone turnover in either hTNF-transgenic mice or WT mice. In vitro, treatment with therapeutically relevant concentrations of bortezomib resulted in increased differentiation of monocytes into osteoclasts and more resorption pits. Molecularly, bortezomib increased the expression of TNF receptor-associated factor 6, c-Fos, and nuclear factor of activated T cells c1 in osteoclast precursors.. In TNF-mediated bone destruction, bortezomib treatment increased synovial osteoclastogenesis and bone destruction. Hence, proteasome inhibition may have a direct bone-resorptive effect via stimulation of osteoclastogenesis during chronic arthritis.

Topics: Animals; Arthritis; Bone and Bones; Bone Resorption; Boronic Acids; Bortezomib; Cartilage, Articular; Chronic Disease; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Osteoclasts; Osteoprotegerin; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyrazines; RANK Ligand; Synovial Membrane; Tumor Necrosis Factor-alpha

Vascular calcification is frequent in patients with chronic kidney disease. Osteoprotegerin (OPG, a soluble factor which blocks osteoclast differentiation) has recently been implicated in the genesis of vascular calcification. Given that OPG can bind the pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we hypothesized that the TRAIL protein is involved in the formation of vascular calcification both in vitro and in vivo. Using an immunohistochemical approach, we evaluated TRAIL and OPG expression on aortic valves slides from non-uremic and uremic wild type and apolipoprotein knockout (Apo E(-/-) ) mice. We also tested the in vitro effects of TRAIL on cultured primary human vascular smooth muscle cells (hVSMC). We further assayed serum soluble TRAIL (sTRAIL) levels in hemodialysis patients and correlated them with vascular calcification scores. Our results demonstrated that: (i) TRAIL and OPG were expressed inside the atheroma plaque in non-uremic ApoE(-/-) mice, but not in wild type mice; and (ii) uremia enhanced the expression levels. TRAIL enhanced the phosphate-induced mineralization of hVSMCs in a dose-dependent manner. In clinical terms, we demonstrated that sTRAIL is depressed in the sera of hemodialysis patients, but was not correlated with vascular calcification. Our results suggest that TRAIL may be involved in the formation of vascular calcification in certain experimental settings; however, its role in chronic kidney disease patients requires further evaluation.

Topics: Aged; Animals; Apolipoproteins E; Calcinosis; Cells, Cultured; Chronic Disease; Disease Models, Animal; Female; Humans; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Osteoprotegerin; Plaque, Atherosclerotic; Renal Dialysis; TNF-Related Apoptosis-Inducing Ligand; Uremia

Osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL) and fibroblast growth factor-23 (FGF-23) play a central role in renal osteodystrophy. We evaluated OPG/RANKL and FGF-23 levels in 51 children with chronic kidney disease (CKD) [n = 26 stage 3 or 4 (CKD3-4) and n = 25 stage 5 (CKD5)] and 61 controls. Any possible association with intact parathyroid hormone (iPTH) and bone turnover markers was also investigated. The OPG levels were lower in the CKD3-4 group (p < 0.001) and higher in the CKD5 group (p < 0.01) than in the controls, while RANKL levels did not differ. The FGF-23 levels were higher in both patient groups (p < 0.0001), while the levels of phosphate and iPTH were higher only in the CKD5 group (p < 0.0001). There were independent positive correlations between OPG and RANKL (β = 0.297, p < 0.01) and FGF-23 (β = 0.352, p < 0.05) and a negative correlation with the bone resorption marker TRAP5b (β = -0.519, p < 0.001). OPG was positively correlated with iPTH (R = 0.391, p < 0.01). An independent positive correlation between FGF-23 and phosphate (β = 0.368, p < 0.05) or iPTH (β = 0.812, p < 0.0001) was noted. In conclusion, we found that higher OPG levels in patients with CKD stage 5 correlated with the levels of RANKL, FGF-23, iPTH, and TRAP5b. These findings may reflect a compensatory mechanism to the negative balance of bone turnover. High FGF-23 levels in early CKD stages may indicate the need for intervention to manage serum phosphate (Pi) levels.

Topics: Acid Phosphatase; Analysis of Variance; Biomarkers; Bone Remodeling; Case-Control Studies; Child; Child, Preschool; Chronic Disease; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Greece; Humans; Isoenzymes; Kidney Diseases; Male; Osteoprotegerin; Parathyroid Hormone; Phosphates; RANK Ligand; Regression Analysis; Severity of Illness Index; Tartrate-Resistant Acid Phosphatase

Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been proposed to be the replacement of renal osteodystrophy by the Organization of Kidney Disease: Improving Global Outcomes since 2005 because the mineral disorder is not confined to the skeleton in CKD. Accordingly, laboratory and imaging tests have been emphasized for the clinical assessment of patients with CKD besides renal biopsy. The objective of the current study was to investigate whether osteoprotegerin (OPG) could be made a useful biomarker for early diagnosis of CKD-MBD.. Sixty pre-dialysis patients with CKD 1-5 were enrolled in this study. The serum calcium, phosphorus, blood urea nitrogen, creatinine, alkaline phosphatase, Osteocalcin, Calcitonin, intact parathyroid hormone and OPG were measured. Bone mineral densities of the lumbar spine (L2-L4), femoral neck, Ward's triangle and trochanter were measured by dual-energy X-ray absorptiometry.. Among all measured serum bone metabolism indexes, the changing of serum OPG level happened at the earliest time (CKD 3) and its correlation coefficient with estimated glomerular filtration rate (eGFR) was also the highest (r = -0.601, P = 0.001). In the multivariable analysis that included sex, age and eGFR as controlling factors, the serum OPG correlated with the bone mineral density (BMD) of Ward's triangle (r = -0.390, P = 0.041).. Serum OPG may be a useful biomarker for early diagnosis of CKD-MBD.

Topics: Absorptiometry, Photon; Adult; Analysis of Variance; Biomarkers; Bone Density; China; Chronic Disease; Chronic Kidney Disease-Mineral and Bone Disorder; Early Diagnosis; Female; Femur; Femur Neck; Glomerular Filtration Rate; Humans; Kidney Diseases; Lumbar Vertebrae; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

Osteoprotegerin (OPG), a cytokine that regulates bone resorption, has been implicated in the process of vascular calcification and stiffness.. Serum OPG was measured in 351 participants with chronic kidney disease (CKD) from one site of the Chronic Renal Insufficiency Cohort Study. Cortical bone mineral content (BMC) was measured by quantitative computed tomography in the tibia. Multivariable linear regression was used to test the association between serum OPG and traditional cardiovascular risk factors, measures of abnormal bone and mineral metabolism, and pulse wave velocity.. Higher serum OPG levels were associated with older age, female gender, greater systolic BP, lower estimated GFR, and lower serum albumin. OPG was not associated with measures of abnormal bone or mineral metabolism including serum phosphorus, albumin-corrected serum calcium, intact parathyroid hormone, bone-specific alkaline phosphatase, or cortical BMC. Among 226 participants with concurrent aortic pulse wave velocity measurements, increasing tertiles of serum OPG were associated with higher aortic pulse wave velocity after adjustment for demographics, traditional vascular risk factors, and nontraditional risk factors such as estimated GFR, albuminuria, serum phosphate, corrected serum calcium, presence of secondary hyperparathyroidism, serum albumin, and C-reactive protein or after additional adjustment for cortical BMC in a subset (n = 161).. These data support a strong relationship between serum OPG and arterial stiffness independent of many potential confounders including traditional cardiovascular risk factors, abnormal bone and mineral metabolism, and inflammation.

Topics: Aged; Analysis of Variance; Aorta; Biomarkers; Bone Density; Cardiovascular Diseases; Chi-Square Distribution; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Osteoprotegerin; Pulsatile Flow; Regional Blood Flow; Risk Assessment; Risk Factors; Tibia; Tomography, X-Ray Computed; United States; Up-Regulation

Bone mass loss is a major complication of chronic cholestatic liver disease (CCD). However, the long-term impact of CCD on bone mass acquisition is unknown. We longitudinally assessed bone mineral density (BMD) and factors involved in bone remodeling in 9 children and adolescents with CCD Child-Pugh A (5 boys/4 girls) and in 13 controls (6 boys/7 girls). The groups were evaluated twice, at baseline (T0) and after 3 years (T1), when osteocalcin, deoxypyridinoline, 25-hydroxyvitamin-D, parathyroid hormone, insulin-like growth factor-I (IGF-I), and BMD (L1-L4, proximal femur and total body) were determined. Serum levels of receptor activator for nuclear factor kB ligand (RANKL) and osteoprotegerin were measured only at T1. Lumbar spine BMD was reanalyzed twice: after adjustment for bone age and to compensate for the height factor. Volumetric density was also estimated mathematically in L2-L4. The BMD of L1-L4 was lower in the CCD group (Z-score at T0: control = -1.2 ± 0.8 vs CCD = -2.2 ± 1.4, P < 0.05; T1: control = -0.7 ± 0.8 vs CCD = -2.1 ± 1.1, P < 0.05). Osteocalcin and deoxypyridinoline were similar for the two groups. The CCD group presented lower IGF-I (Z-score at T1: control = 1.4 ± 2.8 vs CCD = -1.5 ± 1.0, P < 0.05) and RANKL (control = 0.465 ± 0.275 vs CCD = 0.195 ± 0.250 pM, P < 0.05) than control. Children with compensated CCD Child-Pugh A showed early impairment of bone acquisition, with the impact being more severe in an initial phase and then tapering in a slowly progressive way. Reduction in endocrine IGF-I has a crucial role in this process.

Topics: Adolescent; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Case-Control Studies; Child; Cholestasis, Intrahepatic; Chronic Disease; Female; Humans; Longitudinal Studies; Male; Osteoprotegerin; RANK Ligand

Periapical chronic lesion formation involves activation of the immune response and alveolar bone resorption around the tooth apex. However, the overall roles of T helper type 1 (Th1), Th2, and T-regulatory cell (Treg) responses and osteoclast regulatory factors in periapical cysts and granulomas have not been fully determined. This study aimed to investigate whether different forms of apical periodontitis, namely cysts and granulomas, show different balances of Th1, Th2 regulators, Treg markers, and factors involved in osteoclast chemotaxis and activation.. Gene expression of these factors was assessed using quantitative real-time polymerase chain reaction, in samples obtained from healthy gingiva (n = 8), periapical granulomas (n = 20), and cysts (n = 10).. Periapical cysts exhibited a greater expression of GATA-3, while a greater expression of T-bet, Foxp3, and interleukin-10 (IL-10) was seen in granulomas. The expression of interferon-gamma, IL-4, and transforming growth factor-beta was similar in both lesions. Regarding osteoclastic factors, while the expression of SDF-1alpha/CXCL12 and CCR1 was higher in cysts, the expression of RANKL was significantly higher in granulomas. Both lesions exhibited similar expression of CXCR4, CKbeta8/CCL23, and osteoprotegerin, which were significantly higher than in control.. Our results showed a predominance of osteoclast activity in granulomas that was correlated with the Th1 response. The concomitant expression of Treg cell markers suggests a possible suppression of the Th1 response in granulomas. On the other hand, in cysts the Th2 activity is augmented. The mechanisms of periradicular lesion development are still not fully understood but the imbalance of immune and osteoclastic cell activity in cysts and granulomas seems to be critically regulated by Treg cells.

Topics: Adult; Alveolar Bone Loss; Chemokine CCL3; Chemokine CXCL12; Chemokines, CC; Chemotaxis; Chronic Disease; Forkhead Transcription Factors; GATA3 Transcription Factor; Gene Expression; Humans; Interferon-gamma; Interleukin-10; Middle Aged; Osteoclasts; Osteoprotegerin; Periapical Granuloma; Radicular Cyst; RANK Ligand; Receptors, CCR1; Receptors, CXCR4; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells

Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship between bone damage and modulation of bone remodeling-specific gene expression profiles. Our hypothesis was that bone damage observed in young adult rats after binge alcohol exposure is associated with differential expression of bone remodeling-related gene expression. We further hypothesized that this differential gene expression specific to bone remodeling (bone resorption or formation related) would be influenced by the duration of binge alcohol exposure. Binge alcohol (3 g/kg, i.p.) was administered on 3 consecutive days each week, for 1 or 4 weeks, to adult male rats. Matched control animals were injected with an equal volume of isotonic saline. Lumbar vertebrae, L4-5, were analyzed for the presence of bone damage by quantitative computed tomography and compressive strength analysis. Total RNA was isolated from an adjacent vertebrae (L3), and whole transcriptome gene expression data were obtained for each sample. The expression levels of a subset of bone formation and resorption-associated differentially expressed genes were validated by quantitative reverse transcriptase-polymerase chain reaction. Bone loss was not observed after 1 week of treatment but was observed after four binge alcohol cycles with a 23% decrease in cancellous bone mineral density and 17% decrease in vertebral compressive strength compared with control values (P < 0.05). We observed that the duration of binge alcohol treatment influenced the modulation of expression profiles for genes that regulate the bone formation process. The expression of key bone formation-related marker genes such as osteocalcin and alkaline phosphatase were significantly reduced (P < 0.05) after acute binge alcohol exposure, and expression of regulators of osteoblast activity such as bone morphogenetic proteins and parathyroid hormone receptor displayed significantly (P < 0.05) decreased differential expression. The expression of sclerostin, a key canonical Wnt inhibitory protein, was significantly increased after acute binge alcohol treatment. The expression of important regulators of osteoclast maturation and activity such as NF-kapp

Topics: Acute Disease; Alcoholism; Alcohols; Alkaline Phosphatase; Animals; Bone and Bones; Bone Remodeling; Bone Resorption; Chronic Disease; Gene Expression; Interleukin-6; Lumbar Vertebrae; Male; NF-kappa B; Osteocalcin; Osteoprotegerin; RANK Ligand; Rats; Rats, Sprague-Dawley

Cardiovascular disease is the leading cause of death in the chronic kidney disease (CKD) population. The mechanisms of vascular damage are not fully understood. The objective of this study was to prospectively investigate the importance of novel mediators of vascular damage, in conjunction with vascular calcification (VC), on survival.. A total of 134 subjects [60 haemodialysis (HD), 28 peritoneal dialysis (PD) and 46 CKD stage 4] were studied. All survivors completed 40 months of follow-up. VC was measured using multi-slice spiral CT of the superficial femoral artery. Circulating osteoprotegerin (OPG), Fetuin-A and high sensitivity C-reactive protein (hs-CRP) were measured in addition to standard clinical biochemical analysis.. After a 40-month follow-up, 31 patients had died (27 men and 4 women). Of 31 subjects, 31 had evidence of significant VC. The majority of deaths were in the HD group (48%), 36% were PD subjects and 16% were CKD subjects. The outcome of interest was survival at the end of follow-up. Multivariate logistical regression analysis revealed male gender [OR 8.06 (1.34-48.450) P = 0.02], OPG >25 pmol/L [OR 5.31(1.35-20.88) P = 0.02] and hypoalbuminaemia [OR 0.26 (0.12-0.56) P < 0.01], were associated with increased odds of death.. We have previously reported that VC and low albumin predict death in CKD stages 4 and 5 over a 2-year follow-up period. These data show that OPG, independent of CRP, is also associated with a negative outcome. The mechanisms remain to be elucidated; however, it is likely that they are associated with vascular damage through mechanisms in addition to VC.

Topics: C-Reactive Protein; Calcinosis; Cause of Death; Chronic Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Severity of Illness Index; Survival Rate; Time Factors; Vascular Diseases

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Osteoprotegerin (OPG) could play a key role in bone-vascular calcification imbalance and could be a marker of vascular calcification extent and progression. The purpose of this study was to evaluate relationships between vascular risk biomarkers (including classic risk factors and OPG) and coronary artery calcification (CAC) extent in chronic kidney disease (CKD) patients and to establish within the markers the appropriate cut-off value to predict CAC.. A total of 133 non-dialyzed CKD patients at various stages of kidney disease [75 males/58 females, median age: 69.9 (27.4-94.6)] were enrolled, excluding extrarenal replacement therapy patients. All underwent chest multidetector computed tomography for CAC scoring. Blood samples were collected for measurement of vascular risk markers (kidney disease, inflammation, nutrition, calcium phosphate and OPG). A potential relationship between CAC and these biological markers was investigated, and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of involved markers that best predicted the presence of CAC.. After adjustment for age, diabetes, smoking and gender, among biological markers, only low-estimated glomerular filtration rate using Modification of Diet in Renal Disease [OR = 3.63 (1.10-12.02)], high FEPO(4) [OR = 3.99 (1.17-13.6)] and high OPG levels [OR = 8.54 (2.14-34.11)] were associated with the presence of CAC. A protective effect of 1.25(OH)(2) vitamin D [OR = 0.20 (0.05-0.79)] and LDL cholesterol [OR = 0.27 (0.08-0.94)] on CAC was also observed. ROC curve analysis showed that the OPG best cut-off value predicting CAC was 757.7 pg/mL.. These results suggest that a CAC increase is strongly associated with a plasma OPG increase in CKD patients. The values of OPG >757.7 pg/mL allow us to predict the presence of CAC in these patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Calcinosis; Chronic Disease; Coronary Artery Disease; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; ROC Curve

Cardiovascular disease is the major cause of morbidity and mortality in chronic kidney disease (CKD) and early biomarkers are required which can predict disease and death in such patients. The aim of our study was to investigate if osteoprotegerin (OPG) could be a predictor of coronary artery calcification (CAC) and mortality in CKD.. A total of 77 outpatients (32 with pre-dialysis CKD and 45 undergoing hemodialysis) were followed-up during 2 years. Measurements of CAC were performed using Siemens Multidetector CT software and calcium scores were measured according to the Agatston method.. OPG was an independent predictor of the Agatston score for CAC and correlated with the degree of CAC in pre-dialysis patients. A two-sample t-test characterized survivors as having a better glomerular filtration rate, lower Agatston scores, and lower serum levels of OPG. Kaplan-Meier survival curves separated survivors from non-survivors at plasma OPG cut-off levels of <3.1 ng/mL. A multivariable logistic regression analysis showed that OPG was an independent predictor of mortality from all causes in CKD patients.. OPG predicted mortality in CKD patients and could be a valuable biomarker in early detection of CAC in these patients.

Topics: Adult; Aged; Biomarkers; Chronic Disease; Coronary Artery Disease; Female; Humans; Kidney Diseases; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Risk Factors; Survival Rate

It has been demonstrated that genetic variation accounts for approximately half of the variance in periodontitis. The reported association of polymorphisms in the osteoprotegerin (OPG) gene with osteoporosis suggests that the OPG gene may also influence the genetic risk for periodontitis.. We investigated the distribution of OPG gene polymorphisms in 49 patients with aggressive (n = 14) or chronic (n = 35) periodontitis and 49 control subjects without periodontitis, using polymerase chain reaction (PCR)-restriction fragment length polymorphism and PCR-single strand conformation polymorphism followed by direct sequencing.. A total of seven known polymorphisms and one new mutation, G373A, were identified. The T950 and G1181 alleles were more common in patients with periodontitis (P = 0.028 and P = 0.047, respectively) than in control subjects. Especially, G1181 allele was associated with patients with aggressive periodontitis.. The TG haplotype of T950C and G1181C polymorphisms in the OPG gene may be useful genetic markers for the prediction of periodontitis. Further studies in a larger population are required to determine whether these alleles directly contribute to periodontitis susceptibility.

Topics: Adult; Case-Control Studies; Chronic Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Osteoprotegerin; Periodontitis; Polymorphism, Genetic; Reference Values; Severity of Illness Index

The aim of this study was to investigate sRANKL and OPG levels in serum and synovial fluid (SF) and to evaluate their relations in patients with RA in comparison to those with non-erosive arthritis (NEA). The study included 45 unselected RA patients with knee joint effusions and 27 patients with knee joint effusions because of NEA. Serum and SF samples were investigated isochronously. OPG and sRANKL were measured by ELISA assays. In RA, sRANKL levels were higher in serum than in SF (P = 0.007). In contrast, the NEA revealed higher sRANKL in SF compared to the serum (P = 0.001). Though in RA the average levels of sRANKL(ser) were 5.6 times and of sRANKL(syn) 1.5 times higher than in NEA, the differences were not significant. The free (unbound) OPG in SF was not significantly different in RA compared to NEA. Also in serum, the measured free OPG was only slightly higher in RA. There were no significant differences between RA and NEA concerning ESR and CRP. Significant correlations could be found between sRANKL(syn )and CRP (r = 0.453; P = 0.005) as well as ESR (r = 0.362; P = 0.033) in RA. Nearly a positive correlation was evident also between sRANKL(syn) and CRP in NEA (r = 0.520; P = 0.08). RA and NEA differ in particular concerning their power and intensity to destruct the juxtaarticular bone. This is the most remarkable finding of this study, that in RA a high part of sRANKL seems to be OPG bound and cleared by the blood stream, but the sRANKL neutralizing capacity of produced OPG in opposite to NEA is not sufficient to prevent osteoclast activation and bone destruction in the RA joint.

Topics: Adult; Arthritis, Rheumatoid; Biomarkers; Blood Sedimentation; C-Reactive Protein; Chronic Disease; Female; Humans; Inflammation; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Solubility; Synovial Fluid

To investigate the expression of key mediators that regulate bone resorption, receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in human periapical granuloma (PG) and radicular cyst (RC) characterized by periapical bone destruction.. Immunohistochemical technique was performed using monoclonal antibody to detect RANKL and OPG expression in PG (n= 20 ) and RC (n= 20 ). As control group, healthy periodontal ligament tissues (n = 6 ) were obtained from teeth with orthodontic indication of extraction.. The RANKL protein expression was significantly higher in PG (43.74 +/- 8.40) and RC (40.33 +/- 7.53) than in control group (15.47 +/- 2.59, P=0.000) , but no statistical significance could be found between PG and RC groups(P=0.161) .The expression of OPG in PG (27.81 +/- 5.17), RC (26.35 +/- 3.86) and control group (24.33 +/- 3.50) show no statistical significance (P >0.05). Moreover, RANKL/OPG ratio in PG (1.59 +/- 0.26) and RC (1.54 +/- 0.24) was much higher than that in control group (0.64 +/- 0.10, P=0.000), however the ratio of RANKL/OPG showed no significant difference between PG and RC groups (P= 0.504) .. RANKL and OPG were observed in the periapical lesions. RANKL may be responsible for bone resorption in periapical lesions. RANKL and OPG may play an important role in the development of periapical lesions.

Topics: Chronic Disease; Humans; Osteoprotegerin; Periapical Periodontitis; RANK Ligand

The present study aimed to evaluate whether chronic stress (CS) affects ligature-induced periodontal disease and to investigate the impact of CS on the mRNA levels of interleukin (IL)-1beta, -1 receptor antagonist, -6, and -10, interferon-gamma (IFN-gamma), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin in the gingival tissues of rats.. Sixty male Wistar rats were assigned randomly to three groups: G1 (control; non-ligated sites), G2 (periodontal disease), and G3 (periodontal disease associated with restraint stress for 12 hours/day for the entire study). After 30 days, all animals were sacrificed by decapitation. Blood samples were taken, and the concentrations of corticosterone and catecholamines were measured as biomarkers of CS. Marginal tissues around ligated and non-ligated teeth were harvested, and gene expression was assessed by quantitative polymerase chain reaction. Moreover, the area of bone loss (ABL) was determined histometrically.. Data analysis showed that CS increased serum levels of stress biomarkers (P <0.05), ligature placement resulted in a significant ABL compared to non-ligated sites, CS significantly increased the amount of ABL in inflamed sites (P <0.001), and CS significantly increased mRNA levels of proinflammatory (IL-1beta and -6 and IFN-gamma) and anti-inflammatory (IL-10) cytokines and proresorptive factor (RANKL) in ligated sites (P <0.05).. CS significantly increased bone loss resulting from ligature-induced periodontitis by a local increase in proinflammatory and proresorptive factors.

Topics: Alveolar Bone Loss; Animals; Biomarkers; Catecholamines; Chronic Disease; Corticosterone; Gingiva; Inflammation Mediators; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-1beta; Interleukin-6; Male; Osteoprotegerin; Periodontitis; Random Allocation; RANK Ligand; Rats; Rats, Wistar; Receptors, Interleukin-1; RNA, Messenger; Stress, Physiological

This study evaluated the effect of smoking on the gene expression of interleukin-1alpha, -1ra, -6, -8 and -10, tumor necrosis factor-alpha, matrix metalloproteinase (MMP)-2 and -8, receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin, in sites with periodontitis.. Gingival biopsies were divided into three groups: the healthy group (periodontally healthy subjects; n=10); the periodontitis group [subjects with severe chronic periodontitis who never smoked (probing depth>or=7 mm) (n=25)]; and the smoking group (subjects diagnosed with severe chronic periodontitis who smoked>or=1 pack per day for at least 10 years; n=25). Gene and protein expressions were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.. Data analysis demonstrated that, except for MMP-8 and osteoprotegerin, the levels of all factors were increased by inflammation (p<0.001). The levels of interleukin-1alpha, -1ra, -6 and -8, and RANKL, were higher in smokers with periodontitis compared with controls, whereas the levels of interleukin-10, MMP-8 and osteoprotegerin were lower (p<0.001). Smoking lowered the levels of interleukin-1alpha, -8, -10, tumor necrosis factor-alpha, MMP-8 and osteoprotegerin, and increased the levels of interleukin-6 and -1ra in sites with a comparable type of periodontitis (p<0.001).. In conclusion, smoking modulates gene expression in the periodontium, and the influence of smoking on periodontal disease may involve effects of interleukin-6:interleukin-10 and RANKL:osteoprotegerin ratios.

Topics: Analysis of Variance; Case-Control Studies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Humans; Interleukins; Male; Matrix Metalloproteinases; Osteoprotegerin; Periodontitis; RANK Ligand; Reverse Transcriptase Polymerase Chain Reaction; Smoking; Statistics, Nonparametric; Tumor Necrosis Factor-alpha

Receptor activator of nuclear factor-kappa B (NF-kappaB) ligand (RANKL) and osteoprotegerin (OPG) are critical for homeostatic control of osteoclast activity, suggesting their vital roles in the progression of bone loss in periodontitis. In this study, the expression of RANKL and OPG mRNA and the relationship between these factors and periodontopathic bacteria in periodontal tissue were studied.. Gingival tissue and subgingival plaque samples were collected from 15 patients with chronic periodontitis and 15 periodontally healthy subjects. RNA was extracted from the tissue and subjected to reverse transcription-polymerase chain reaction (RT-PCR) using primers specific for RANKL or OPG. Beta-actin was amplified as a control to ensure equal loading. The intensity of RT-PCR products was analyzed by a densitometer in proportion to the intensity of beta-actin. The numbers of Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were determined by quantitative real-time PCR.. Our results showed increased levels of RANKL mRNA in chronic periodontitis tissues. The RANKL/OPG expression ratio was significantly higher in the periodontitis group compared to the healthy control group (P = 0.001). Interestingly, the expression of RANKL (r = 0.64; P <0.001), but not OPG (r = -0.24; P = 0.20), was significantly correlated with increased numbers of P. gingivalis. A. actinomycetemcomitans was detected in only 6.7% of all sites.. Chronic periodontitis was associated with RANKL mRNA upregulation and increased RANKL/OPG mRNA expression ratio. In addition, our data showed for the first time to our knowledge an association between upregulated RANKL levels and the number of P. gingivalis in clinically obtained periodontal tissues.

Topics: Actins; Adult; Age Factors; Aggregatibacter actinomycetemcomitans; Chronic Disease; Dental Plaque; Epidemiologic Methods; Female; Gingiva; Humans; Male; Middle Aged; Osteoprotegerin; Periodontitis; Porphyromonas gingivalis; RANK Ligand; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Sex Factors; Up-Regulation

Periodontitis is an inflammatory bone disease caused by Gram-negative anaerobic bacteria. Osteoclast differentiation is regulated by the balance between receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG). The purpose of this study was to examine the mechanism of OPG production in human gingival fibroblasts (HGF) stimulated by lipopolysaccharide (LPS) from periodontopathic bacteria. The expressions of Toll-like receptor 2 (TLR-2) and TLR-4 in HGF were examined using flow-cytometry. HGF were stimulated with whole cell extracts or LPS from Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis with or without polymyxin B, a LPS inhibitor. In addition, HGF were stimulated with LPS, prostaglandin E(2) (PGE(2)), various agonists of PGE receptors (EP1, EP2, EP3 and EP4 agonists) with or without indomethacin (IND), a prostaglandin synthesis inhibitor. OPG and PGE(2) production was measured using an enzyme-linked immunosorbent assay (ELISA). HGF expressed both TLR-2 and TLR-4. Both A. actinomycetemcomitans and P. gingivalis LPS augmented OPG expression in HGF. Whole cell extracts from A. actinomycetemcomitans and P. gingivalis augmented OPG production by HGF; the augmentation was suppressed by polymyxin B. IND suppressed OPG production in LPS-stimulated HGF. PGE(2) stimulated HGF to produce OPG. EP1 and EP2 agonists, but not EP3 and EP4 agonists, increased OPG production by HGF. These results suggest that LPS-induced OPG production by HGF is regulated via EP1 and/or EP2 receptors by endogenously generated PGE(2).

Topics: Cells, Cultured; Chronic Disease; Dinoprostone; Dose-Response Relationship, Drug; Fibroblasts; Gingiva; Humans; Lipopolysaccharides; Osteoprotegerin; Periodontitis; Receptors, Prostaglandin E; Toll-Like Receptor 2; Toll-Like Receptor 4

Receptor activator of nuclear factor-kappaB ligand (RANKL) is responsible for the induction of osteoclastogenesis and bone resorption, whereas its decoy receptor, osteoprotegerin, can directly block this action. Because this dyad of cytokines is crucial for regulating the bone remodelling process, imbalances in their expression may cause a switch from the physiological state to enhanced bone resorption or formation. This study investigated the mRNA expression of RANKL and osteoprotegerin, as well as their relative ratio, in the gingival tissues of patients with various forms of periodontal diseases.. Gingival tissue was obtained from nine healthy subjects and 41 patients, who had gingivitis, chronic periodontitis, generalized aggressive periodontitis, and chronic periodontitis and were receiving immunosuppressant therapy. Quantitative real-time polymerase chain reaction was employed to evaluate the mRNA expression of RANKL and osteoprotegerin in these tissues.. Compared with healthy individuals, patients in all periodontitis groups, but not those with gingivitis, exhibited stronger RANKL expression and a higher relative RANKL/osteoprotegerin ratio. In addition, osteoprotegerin expression was weaker in patients with chronic periodontitis. When patients with generalized aggressive periodontitis and chronic periodontitis were compared, the former exhibited stronger RANKL expression, whereas the latter exhibited weaker osteoprotegerin expression, and there was no difference in their relative ratio. When chronic periodontitis patients were compared with chronic periodontitis patients receiving immunosuppressant therapy, osteoprotegerin, but not RANKL, expression was stronger in the latter.. This study demonstrates that RANKL and osteoprotegerin expression are differentially regulated in various forms of periodontitis, and the relative RANKL/osteoprotegerin ratio appears to be indicative of disease occurrence. This information may confer diagnostic and therapeutic value in periodontitis.

Topics: Adolescent; Adult; Case-Control Studies; Chronic Disease; Female; Gingiva; Humans; Immunocompromised Host; Male; Middle Aged; Osteoprotegerin; Periodontal Attachment Loss; Periodontal Index; Periodontitis; RANK Ligand; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

To investigate the association of polymorphisms in the osteoprotegerin (OPG) and interleukin 1 (IL-1) genes with chronic periodontitis (CP).. One hundred and ninety-four individuals (97 CP patients, 97 controls) were genotyped for the OPG polymorphisms Lys3Asn and Met256Val and for the IL-1 polymorphisms IL-1A (-889C/T) and IL-1B (+3953C/T).. The homozygous variants coding for Lys3 were present at a higher frequency, whereas Asn3 and Met256 were present at a lower frequency in CP patients/controls (Lys3: 31%/25%, Asn3: 23%/32% and Met256: 66%/73%). Heterozygosity for Lys3Asn was observed at a higher frequency in CP patients/controls (46%/43%). Homozygosity for the Val256 genotype was observed in two CP patients (one in controls). Met256Val heterozygosity was more prevalent in CP patients/controls (32%/20%). All differences were statistically not significant between CP patients and controls. In contrast, both IL-1 polymorphisms were statistically significant. The heterozygous variant for IL-1A was present in 32% of the CP patients and in 20% of the controls (homozygosity (patients/controls) CC: 10%/21% and TT: 55%/33%). Heterozygosity for IL-1B was observed in 37% of the CP patients versus 34% in the controls (homozygosity (patients/controls) CC: 26%/57% and TT: 37%/9%).. While the association between the IL-1 polymorphisms and CP was confirmed, no association between the OPG polymorphisms and CP could be found.

Topics: Adult; Alleles; Case-Control Studies; Chronic Disease; DNA Primers; Female; Genotype; Humans; Interleukin-1; Male; Middle Aged; Osteoprotegerin; Periodontitis; Polymorphism, Genetic

Chronic periodontitis (CP) risk is influenced by environmental and genetic factors. Using a case-control design, we tested for associations between CP and selected DNA sequence variations (single nucleotide polymorphisms [SNPs]) in or near genes coding for proteins that play a role in the pathogenesis of this disease.. DNA was analyzed from 219 whites who were examined clinically. Cases (N=137) were >or=35 years of age with eight or more teeth having >or=5 mm of proximal clinical attachment loss. Controls (N=82) were >or=45 years of age with minimal or no proximal attachment loss or pocketing. Nine diallelic polymorphisms (gene and SNP descriptor) were studied in subjects: cytotoxic T-lymphocyte antigen-4 (CTLA-4, 49 A>G), human beta-defensin-1 (DEFB1, 692 G>A), intercellular adhesion molecule-1 (ICAM-1, 1548 A>G), Fas ligand (fasL, -844 C>T), inducible costimulator (ICOS, 3990 G>T), interleukin-6 (IL-6, -174 G>C), cysteine-cysteine chemokine receptor-5 (CCR5, 59653 C>T), osteoprotegerin (OPG, 245 T>G), and osteopontin (OPN, 707 C>T). Genotypes were determined using an automated fluorogenic 5'-nuclease, polymerase chain reaction-based assay. Gender and smoking history (pack-years) were included as covariates in logistic regression analyses.. Heavy smoking (>10 pack-years) and male gender were significantly associated with disease (P<0.001). For all SNPs tested, the allele frequencies and distributions of genotypes did not differ between cases and controls (P>0.05). No unadjusted or adjusted odds ratios (comparing genotypes in cases versus controls) were significantly different than 1.0 (P>0.05) under any additive, dominant, or recessive inheritance model.. None of the SNPs tested were strongly associated with generalized severe chronic periodontitis in North American whites. A potentially more fruitful approach in future studies will be to test for associations between periodontitis and haplotype blocks constructed from either multiple SNPs in candidate gene regions or from panels of markers that span the entire genome.

Topics: Adult; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; beta-Defensins; Case-Control Studies; Chronic Disease; CTLA-4 Antigen; Fas Ligand Protein; Female; Genetic Predisposition to Disease; Glycoproteins; Humans; Inducible T-Cell Co-Stimulator Protein; Intercellular Adhesion Molecule-1; Interleukin-6; Logistic Models; Male; Membrane Glycoproteins; Middle Aged; Osteopontin; Osteoprotegerin; Periodontitis; Polymorphism, Single Nucleotide; Receptors, CCR5; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sialoglycoproteins; Tumor Necrosis Factors

Recent findings have suggested that osteoclastogenesis is directly regulated by receptor activator of nuclear factor-kappa B ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG). However, no studies have described interactions of OPG/RANKL and the gp130 cytokine family in periodontal disease. This study aimed to identify and quantify OPG/RANKL in the gingival crevicular fluid (GCF) and connective tissue of patients with periodontitis, and to clarify possible correlations with disease severity and interleukin-6 (IL-6) cytokines.. Ninety-five sites in 20 patients with generalized chronic periodontitis were divided into four groups by site based on probing depth (PD) and bleeding on probing (BOP). In periodontitis patients, GCF was obtained using sterile paper strips from clinically healthy sites (PD 6 mm with BOP, n = 27). Fourteen clinically healthy sites from four periodontally healthy individuals were used as the control group. The levels of OPG, RANKL and two gp130 cytokines - IL-6 and oncostatin M (OSM) - in the GCF were determined by an enzyme-linked immunosorbent assay (ELISA) and are expressed as total amounts (pg/site). Immunohistochemical localization of OPG- and RANKL-positive cells was also performed on gingival connective tissues harvested from patients with periodontitis (inflammatory group, n = 8 biopsies) and from non-diseased individuals (healthy group, n = 8 biopsies).. GCF RANKL, but not OPG, was elevated in diseased sites of patients with periodontitis. However, the expressions of OPG and RANKL showed no correlation with disease severity (r = 0.174 and 0.056, respectively), but the content of RANKL in the GCF was significantly positively correlated with those of IL-6 (r = 0.207) and OSM (r = 0.231) (p < 0.01). Immunohistochemical staining showed that RANKL-positive cells were significantly distributed in the inflammatory connective tissue zone of diseased gingiva, compared with those of samples from non-diseased persons (p < 0.01). However, few OPG-positive cells were found in connective tissue zones of either the diseased gingiva or healthy biopsies.. These findings imply that in this cross-sectional study of GCF, RANKL, IL-6 and OSM were all prominent in periodontitis sites, whereas OPG was inconsistently found in a few samples of diseased sites but was undetectable in any of the control sites. The results also imply that the expression of RANKL was positively correlated with IL-6 and OSM in the GCF.

Topics: Adult; Analysis of Variance; Carrier Proteins; Case-Control Studies; Chronic Disease; Cytokines; Female; Gingiva; Gingival Crevicular Fluid; Glycoproteins; Humans; Immunohistochemistry; Interleukin-6; Male; Membrane Glycoproteins; Middle Aged; Oncostatin M; Osteoprotegerin; Periodontal Index; Periodontitis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Statistics, Nonparametric

Transforming growth factor beta-1 (TGF beta-1) is a potent inducer of fibrosis and has been shown to be essential for the development of bone marrow fibrosis in an animal model of idiopathic myelofibrosis (IMF). IMF belongs to the Philadelphia chromosome negative chronic myeloproliferative disorders (Ph(-) CMPD). Megakaryocytes and platelets have been suggested as the major cellular source of TGF beta-1 in IMF. The osteoclastogenesis inhibitory factor osteoprotegerin (OPG) seems to be regulated by TGF beta-1 and substantial involvement of OPG expression in the process of osteosclerosis in IMF has recently been suggested. In order to determine TGF beta-1 expression in IMF and other Ph(-) CMPD, total bone marrow cells as well as laser-microdissected megakaryocytes were quantitatively analysed by real-time RT-PCR. OPG mRNA expression in fibrotic IMF was correlated with TGF beta-1 mRNA expression in a case-specific manner. Both OPG and TGF beta-1 were detected immunohistochemically in order to delineate cellular origin. When total bone marrow cells were investigated, TGF beta-1 mRNA expression was increased in some but not all cases of IMF (n = 21), with highest values in fibrotic cases. Unexpectedly, increased values were also observed in essential thrombocythaemia (ET, n = 11) when compared to non-neoplastic haematopoiesis (n = 38). Megakaryocytes isolated by laser microdissection displayed elevated TGF beta-1 mRNA levels in most of the CMPD samples with no significant differences discernible between fibrotic IMF, polycythaemia vera (PV) and ET. TGF beta-1 protein was predominantly expressed by the myeloid lineage in Ph(-) CMPD and non-neoplastic haematopoiesis, which, however, displayed lower expression. IMF cases with advanced fibrosis concomitantly overexpressed TGF beta-1 and OPG. Immunohistochemically, OPG expression was found in different stromal cells and a subfraction of megakaryocytes. In conclusion, enhanced TGF beta-1 expression occurs in megakaryocytes as well as myeloid cells in Ph(-) CMPD. TGF beta-1 may be necessary, but is not sufficient, to induce bone marrow fibrosis in IMF because non-fibrotic Ph(-) CMPD entities share this feature with IMF and cannot be discriminated from each other on the basis of TGF beta-1 expression.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Bone Marrow Cells; Chronic Disease; Diagnosis, Differential; Female; Gene Expression; Glycoproteins; Hematopoiesis; Humans; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Male; Megakaryocytes; Microdissection; Middle Aged; Myeloproliferative Disorders; Osteoprotegerin; Polycythemia Vera; Primary Myelofibrosis; Protein Array Analysis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thrombocythemia, Essential; Transforming Growth Factor beta; Transforming Growth Factor beta1

The majority of patients with chronic kidney disease (CKD) have excessive vascular calcification; however, most studies demonstrate that a subset of CKD patients do not have, nor develop, vascular calcification despite similar exposure to the uremic environment. This suggests protective mechanisms, or naturally occurring inhibitors, of calcification may be important.. In order to determine the role of three inhibitors, fetuin-A, matrix gla protein (MGP), and osteoprotegerin (OPG) in the vascular calcification observed in patients with CKD-5, we (1) measured serum levels of these inhibitors and compared the levels to calcification assessed by computed tomography (CT); (2) examined arteries from CKD-5 patients by immunostaining for these inhibitors; and (3) examined the expression and effect of these inhibitors in cultured bovine vascular smooth muscle cells (BVSMCs) incubated in serum pooled from uremic patients compared to healthy controls.. There was a negative correlation of coronary artery calcification scores with serum fetuin-A levels (r=-0.30, P= 0.034) and a positive association with OPG levels (r= 0.29, P= 0.045). There was increasing immunostaining for both fetuin-A and MGP in arteries with increasing calcification graded semiquantitatively (P < 0.003). In vitro, fetuin-A added to mineralizing BVSMCs inhibited mineralization (P < 0.001). Compared to normal serum, BVSMCs incubated with uremic serum had a progressive increase in MGP expression with mineralization (P < 0.001) and increased expression of OPG in BVSMCs (P < 0.04).. These data demonstrate that fetuin-A, OPG, and MGP play an important role in the pathogenesis of uremic vascular calcification.

Topics: alpha-2-HS-Glycoprotein; Animals; Blood Proteins; Calcinosis; Calcium-Binding Proteins; Cattle; Cells, Cultured; Chronic Disease; Extracellular Matrix Proteins; Glycoproteins; Humans; Kidney Diseases; Matrix Gla Protein; Muscle, Smooth, Vascular; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vascular Diseases

Osteopenia and osteoporosis are common complications of chronic liver disease (CLD). Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) regulate osteoclastogenesis and bone remodelling, and are involved in several inflammatory diseases. This study investigated the activation state of the RANKL/OPG system and its association with bone loss in CLD.. Serum levels of OPG and sRANKL were determined in 193 patients with CLD and 56 age- and gender-matched healthy controls. Cellular sources of OPG and RANKL were determined immunohistochemically. Dual-energy x-ray absorptiometry was performed to determine bone mineral density (BMD) of lumbar spine and femoral neck.. sRANKL serum levels were significantly elevated in non-cirrhotic, but not cirrhotic patients compared to healthy controls. OPG serum levels were elevated 1.6-fold in non-cirrhotic and 2.8-fold in cirrhotic CLD patients. RANKL+ cells were mainly confined to portal fields, while OPG was broadly expressed. In the cirrhotic subgroup (87 patients) we observed a significantly higher OPG/sRANKL ratio in patients with osteopenia or osteoporosis of the lumbar spine and femoral neck region (T-score < -1) compared to those with normal BMD (T-score > or = -1).. CLD is associated with alterations in RANKL/OPG serum levels, which could modulate bone loss in CLD.

Topics: Adult; Aged; Aged, 80 and over; Bone Density; Bone Diseases, Metabolic; Carrier Proteins; Chronic Disease; Female; Glycoproteins; Humans; Liver Cirrhosis; Liver Diseases; Male; Membrane Glycoproteins; Middle Aged; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Recently, receptor activator of nuclear factor-kappaB ligand (RANKL), its receptor RANK, and the decoy receptor osteoprotegerin (OPG), have been identified as paracrine mediator of bone functions. The balance of RANKL/RANK and OPG is critical for osteoclastogenesis modulation and physiological bone remodeling. Osteopontin (OPN) is an extracellular glycosylate bone phosphoprotein and acts both as chemokine and cytokine. It is produced by osteoclast, macrophages, T cells, hematopoietic cells and vascular smooth muscle cells. It is present particularly at high concentration in the lamina limitans and cement line, suggesting its role in the initiation and termination of the bone turnover. Chronic arthritis are a group of rheumatic pathologies characterized by periodical continuous or desultory use of corticosteroids. The main aims of this study are to evaluate OPG, RANKL and OPN serum concentrations in patients affected by chronic arthritis and to compare the above results with those ones obtained by young healthy population. OPG, RANKL and OPN serum concentration has been measured by ELISA method both in 40 patients affected by chronic arthritis then in young healthy population of 81 subjects. The differences between the two considered groups have been analyzed using unpaired T-Student. The difference between the two groups is significant for considered variables: OPG: t = -6.54, p < 0.001; RANKL: t = -2.71, p = 0.008; OPN: t = 2.55, p = 0.01. These results suggest that RANKL/RANK system,OPG and OPN have important role in patients with chronic arthritis.

Topics: Adult; Arthritis; Carrier Proteins; Case-Control Studies; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Osteopontin; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sialoglycoproteins

Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease (CLD). Recently, two new cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor-kB ligand (RANKL), have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases. Therefore, the aim of our study was to evaluate bone metabolism, bone mineral density (BMD) and OPG/RANKL system in 65 male patients with CLD and in 65 healthy controls. Our patients showed lower BMD values than controls both at lumbar and femoral levels. Moreover, they had an unbalanced bone turnover with an increased resorption phase, as shown by high levels of urinary deoxypyridinoline and a decreased formation phase, as shown by the slightly, but significant, low levels of bone-alkaline phosphatase. Patients showed lower plasma levels of free-testosterone than controls and higher - although not significantly so - plasma levels of 17 beta-estradiol. Furthermore, patients with CLD had higher levels of sex hormone-binding globulin and OPG, and lower levels of 25-hydroxyvitamin D (25-HOD) and IGF-I than the control group, while RANKL levels were similar in the two groups. In conclusion, our data do not confirm the hypothesis that the OPG/RANKL system could exert a key role in the pathogenesis of hepatic osteodystrophy, but rather that the observed increase in OPG levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Amino Acids; Bone Density; Bone Diseases, Metabolic; Carrier Proteins; Chronic Disease; Estradiol; Glycoproteins; Humans; Insulin-Like Growth Factor I; Liver Diseases; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Hormone-Binding Globulin; Testosterone; Vitamin D

We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.

Topics: Acute Disease; Animals; Antibodies, Blocking; Carrier Proteins; CD40 Ligand; Cell Line; Chronic Disease; Cytokines; Glycoproteins; Graft Enhancement, Immunologic; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Male; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-kappa B; Osteoprotegerin; RANK Ligand; Rats; Rats, Inbred Lew; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger

Inflammatory reactions raised in response to periodontopathogens are thought to trigger pathways of periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor receptor activator of nuclear factor-kappaB ligand (RANKL), their respective tissue inhibitors of metalloproteinases (TIMPs) and osteoprotegerin (OPG) in different forms of human periodontal diseases (PDs), and the possible correlation with the expression of inflammatory and regulatory cytokines.. Quantitative polymerase chain reaction (real-time PCR) was performed with gingival biopsies mRNA from aggressive (AP) and chronic periodontitis (CP) patients.. Periodontitis patients exhibit higher expression of all analyzed factors when compared with healthy tissues. The expression of MMPs and RANKL were similar in AP and CP, as well as the expression of TNF-alpha. On the other hand, the expression of TIMPs and OPG was higher in CP, and was associated with lower IFN-gamma and higher IL-10 expression, compared with AP.. It is possible that the pattern of cytokines expressed determines the stable or progressive nature of the lesions and regulates the severity of PD, driving the balance between MMPs and TIMPs, RANKL and OPG expression in the gingival tissues controlling the breakdown of soft and bone tissues and, consequently, the disease severity.

Topics: Adult; Carrier Proteins; Chronic Disease; Cytokines; Epidemiologic Methods; Gene Expression Regulation; Glycoproteins; Humans; Matrix Metalloproteinases; Membrane Glycoproteins; Osteoprotegerin; Periodontal Diseases; Polymerase Chain Reaction; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger; Tissue Inhibitor of Metalloproteinases

To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.. We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.. Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1beta (IL-1beta), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.. OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

Topics: Animals; Arthritis, Rheumatoid; Bone Density; Bone Resorption; Chronic Disease; Glycoproteins; Mice; Mice, Transgenic; Osteoclasts; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Periodontitis is an inflammatory bone disease caused by Gram-negative anaerobic bacteria, but the precise mechanism of bone destruction remains unknown. Activated T lymphocytes secrete receptor activator of NF-kappaB ligand (RANKL) and support the differentiation of monocytes into mature osteoclasts. The purpose of this study was to examine the expression of RANKL and its inhibitor, osteoprotegerin (OPG), in inflamed gingival tissue and to clarify the role of human gingival fibroblasts (HGFs) in osteoclastogenesis regulated by RANKL. HGFs and gingival mononuclear cells (GMCs) were obtained from chronic periodontitis patients during routine periodontal surgery. Expression of OPG and RANKL mRNA in gingival tissue and HGFs was examined with RT-PCR. OPG production was measured using ELISA. Expression of RANKL, CD4, CD8 and CD69 on GMCs was determined by flow-cytometry using RANK-Fc fusion protein and the respective monoclonal antibodies. Osteoclastogenesis by RANKL was assayed by counting the number of tartarate-resistant acid phosphatase (TRAP)-positive cells after culturing human peripheral blood monocytes with recombinant human RANKL and macrophage-colony stimulating factor (M-CSF) for 10 days. OPG and RANKL mRNA were expressed in 80% (16/20) and 25% (5/20) of periodontitis lesions, respectively. OPG, but not RANKL, mRNA was expressed within HGFs. OPG mRNA expression and production by HGFs was augmented by LPS stimulation. All GMC samples expressed CD69, and two of five GMC samples expressed RANKL. The culture supernatant of LPS-stimulated gingival fibroblasts significantly reduced the number of TRAP positive cells generated by culturing monocytes with RANKL and M-CSF. The present study suggests that LPS-stimulated HGFs inhibit monocyte differentiation into osteoclasts through the production of OPG.

Topics: Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Carrier Proteins; Cell Differentiation; Cells, Cultured; Chronic Disease; Culture Media, Conditioned; Fibroblasts; Gingiva; Glycoproteins; Humans; Kinetics; Lectins, C-Type; Lipopolysaccharides; Membrane Glycoproteins; Monocytes; Osteoclasts; Osteoprotegerin; Periodontitis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger; Stem Cells

It is well known that long-term glucocorticoid treatment causes osteoporosis, but the precise mechanism remains unclear. Recently, osteoprotegerin (OPG) has been identified as a cytokine that inhibits osteoclast differentiation. We have previously demonstrated that serum OPG is suppressed by glucocorticoids. Therefore, the present study was carried out to clarify the interrelationships between OPG and other markers of bone metabolism during glucocorticoid treatment. Thirteen patients (7 men, 6 women; 44.1 +/- 5.9 years old) with chronic glomerulonephritis who were to be treated with glucocorticoids for the first time were chosen for this study. Markers of bone metabolism, including serum OPG, osteocalcin (OC), bone-specific alkaline phosphatase activity (bAP), parathyroid hormone (PTH), tartrate-resistant acid phosphatase (TRAP), and bone mineral density (BMD), were measured before and during the treatment period. Glucocorticoids significantly reduced BMD of the lumbar spine in the 6 month treatment period (p < 0.01). Serum OPG was decreased significantly by glucocorticoids within 2 weeks (p < 0.001), and serum TRAP, a marker of bone resorption, was markedly increased (p < 0.001). On the other hand, there were no remarkable changes in serum PTH. Serum OC and bAP, markers of bone formation, were transiently reduced during the treatment period (p < 0.01). Furthermore, only serum OPG was positively and independently correlated with percentage BMD of age-matched reference (%AMR). These findings imply that glucocorticoid-induced bone loss develops rapidly via enhanced bone resorption and suppressed bone formation. Moreover, the increased bone resorption caused by glucocorticoids may be, at least in part, mediated by inhibition of OPG, not increment of PTH.

Topics: Adult; Biomarkers; Bone and Bones; Chronic Disease; Female; Glomerulonephritis; Glucocorticoids; Glycoproteins; Humans; Male; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Regression Analysis; Statistics, Nonparametric

Topics: Bone Neoplasms; Chronic Disease; Glycoproteins; Models, Biological; Neural Conduction; Osteoclasts; Osteolysis; Osteoprotegerin; Pain; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spinal Cord; Synaptic Transmission