vitamin-k-semiquinone-radical and Osteoarthritis

Vitamin K is essential for the carboxylation of the vitamin K-dependent proteins that are responsible for the suppression of matrix calcification. The use of vitamin K antagonists (VKAs) in patients with cardiovascular diseases could affect protein carboxylation and lead to the development of osteoarthritis (OA). This review aims to summarise the current evidence for the relationship between VKAs and OA. The literature search revealed that in observation studies, good vitamin K status, as reflected by the circulating level or protein carboxylation status of vitamin K, is associated positively with improved joint structural and functional indices and negatively associated with OA incidence. By contrast, in limited retrospective and prospective studies, the use of VKAs is associated positively with OA occurrence and knee/hip replacement. Pharmacological interactions between VKAs and various OA therapeutic agents exist and require careful monitoring and dosing. In conclusion, further epidemiological studies are warranted to verify the relationship between VKA use and OA to strengthen the evidence. Given that VKA use exerts potentially negative effects on joint health, intervention is required to protect the quality of life and mobility of patients.

Topics: Anticoagulants; Fibrinolytic Agents; Humans; Osteoarthritis; Prospective Studies; Quality of Life; Retrospective Studies; Vitamin K

Vitamin K‑dependent proteins (VKDPs) are a group of proteins that need vitamin K to conduct carboxylation. Thus far, scholars have identified a total of 17 VKDPs in the human body. In this review, we summarize three important emerging VKDPs: Growth arrest‑specific protein 6 (Gas 6), Gla‑rich protein (GRP) and periostin in terms of their functions in physiological and pathological conditions. As examples, carboxylated Gas 6 and GRP effectively protect blood vessels from calcification, Gas 6 protects from acute kidney injury and is involved in chronic kidney disease, GRP contributes to bone homeostasis and delays the progression of osteoarthritis, and periostin is involved in all phases of fracture healing and assists myocardial regeneration in the early stages of myocardial infarction. However, periostin participates in the progression of cardiac fibrosis, idiopathic pulmonary fibrosis and airway remodeling of asthma. In addition, we discuss the relationship between vitamin K, VKDPs and cancer, and particularly the carboxylation state of VKDPs in cancer.

Topics: Animals; Cell Adhesion Molecules; Humans; Intercellular Signaling Peptides and Proteins; Myocardial Infarction; Osteoarthritis; Renal Insufficiency, Chronic; Vitamin K

Vitamin K is a cofactor of γ-glutamyl carboxylase, which plays an important role in the activation of γ-carboxyglutamate (gla)-containing proteins that negatively regulate calcification. Thus, vitamin K status might be associated with osteoarthritis (OA), in which cartilage calcification plays a role in the pathogenesis of the disease. This review collates the evidence on the relationship between vitamin K status (circulating or dietary intake level of vitamin K, or circulating uncarboxylated gla proteins) and OA from human observational studies and clinical trial, to examine its potential as an agent in preventing OA. The current literature generally agrees that a sufficient level of vitamin K is associated with a lower risk of OA and pathological joint features. However, evidence from clinical trials is limited. Mechanistic study shows that vitamin K activates matrix gla proteins that inhibit bone morphogenetic protein-mediated cartilage calcification. Gla-rich proteins also inhibit inflammatory cascade in monocytic cell lines, but this function might be independent of vitamin K-carboxylation. Although the current data are insufficient to establish the optimal dose of vitamin K to prevent OA, ensuring sufficient dietary intake seems to protect the elderly from OA.

Topics: Biomarkers; Calcium; Dietary Supplements; Disease Susceptibility; Humans; Osteoarthritis; Population Surveillance; Vitamin K; Vitamin K Deficiency

Osteoarthritis (OA) is a chronic degenerative joint disease, in which metabolic imbalance in bone is observed. The pathological mechanism of metabolic imbalance is not clear yet, but the nutritional factors, particularly the vitamins, might be intrinsic to the development and progression of OA. In this review article, we have explored databases such as PubMed, Scopus, and Google Scholar articles until the beginning of 2017 and reviewed the role of fat-soluble vitamins in pathological and therapeutic aspects of OA. Vitamin D plays an important role in the development and maintenance of the skeleton, as well as bone and cartilage metabolism, and its deficiency is implicated in the pathological process of OA. Vitamin E enhances chondrocyte growth and exhibits an anti-inflammatory activity, as well as plays an important role in the prevention of cartilage degeneration. In human OA cartilage, vitamin K deficiency produces abnormal growth plate calcification and inappropriate mineralization of cartilage. Thus, these fat-soluble vitamins play a key role in the pathophysiology of OA, and supplementation of these vitamins may provide innovative approaches for OA management. However, vitamin A has a different role, which is a regulator of cartilage and skeletal formation. When metabolite levels of vitamin A are elevated in synovial fluid, they appear to drive OA development. The role of inhibitors of vitamin A here remains unclear. More investigations are needed to examine the effects of fat-soluble vitamins on the various molecular pathways of OA, as well as to assess the efficacy and safety of their usage clinically.

Topics: Humans; Osteoarthritis; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

Gla-rich protein (GRP) or unique cartilage matrix-associated protein (Ucma), the newest member of vitamin K dependent proteins, carries exceptionally high number of γ-carboxyglutamic acid (Gla) residues which contributes to its outstanding capacity of binding with calcium in the extracellular environment indicating its potential role as a global calcium modulator. Recent studies demonstrated a critical function of GRP in the regulation of different pathophysiological conditions associated with vascular and soft tissue calcification including cardiovascular diseases, osteoarthritis, inflammation, and skin and breast carcinomas. These findings established an important relationship between γ-carboxylation of GRP and calcification associated disease pathology suggesting a critical role of vitamin K in the pathophysiological features of various health disorders. This review for the first time summarizes all of the updated findings related to the functional activities of GRP in the pathogenesis of several diseases associated with vascular and soft tissue mineralization, osteoarthritis, inflammation, and carcinoma. The outcome of this review will improve the understanding about the role of GRP in the pathogenesis of tissue calcification and its associated health disorders, which should in turn lead to the design of clinical interventions to improve the condition of patients associated with these health disorders.

Topics: Animals; Calcinosis; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Intracellular Signaling Peptides and Proteins; Neoplasms; Osteoarthritis; Proteins; Vitamin K

Aside from its important role in blood clotting, vitamin K is an important dietary factor in regulating bone and cartilage mineralization. The vitamin K requirements to maintain musculoskeletal health may be more than the current recommendations and subclinical vitamin K deficiency may be involved in the pathogenesis of osteoporosis and osteoarthritis. Observational studies suggest that diets low in vitamin K are associated with increased risk of fractures and osteoarthritis in older adults. However, so far randomized controlled trials of vitamin K supplementation in Caucasian populations have not shown clinically significant improvements in bone mineral density at major skeletal sites. Supplementation with vitamin K may reduce the risk of fractures, but this conclusion comes from clinical trials with methodological limitations. At this time, only one randomized controlled trial has examined the effect of vitamin K supplementation on radiographic hand osteoarthritis and found no overall effect. Large well-designed randomized controlled trials are needed to compare the efficacies of vitamin K1 and K2 on fractures and osteoarthritis among older adults. In summary, currently there is not enough evidence to recommend the use of vitamin K supplements for the prevention of bone loss, fractures, or osteoarthritis in postmenopausal women.

Topics: Aging; Animals; Female; Health Status; Humans; Musculoskeletal Development; Musculoskeletal Physiological Phenomena; Musculoskeletal System; Osteoarthritis; Osteoporosis, Postmenopausal; Postmenopause; Vitamin K; Vitamin K Deficiency

To investigate the physiological roles of vitamin K analogues in bone metabolism, especially in osteoporosis, we have developed a sensitive and simple analysis system for vitamin K analogues in the serum and bone. After the separation of vitamin K analogues on a reversed-phase column, the analogues were reduced once in a platinum catalyst reduction column on-line and then monitored quantitatively by electrochemical detector (EICOM ECD-300) operated in the oxidation mode (+0.6 V vs. Ag/AgCl). The detection limits at a signal-to-noise ratio of 3 were 2-10 pg for vitamin K analogues. We also investigated the extraction procedures for the vitamin K analogues from serum and bone. Quantitative recoveries from serum and bone were obtained in the range of 80-101% for vitamin K analogues. We could determine both the circulating vitamin K levels in osteoporotic patients and the vitamin K contents in trabecular and cortical bone of osteoarthritis.

Topics: Animals; Bone and Bones; Catalysis; Chromatography, High Pressure Liquid; Electrochemistry; Humans; Osteoarthritis; Osteoporosis; Oxidation-Reduction; Platinum; Rats; Sensitivity and Specificity; Vitamin K

The connective tissues are a complex organisation of tissues, cells and intercellular materials spread throughout the body and are subject to a large number of diseases. Such complexity makes the study of the metabolism of the connective tissues in health and more particularly in disease states difficult if one uses conventional biochemical methodology. Fortunately the techniques of quantitative cytochemistry, as developed in recent years, have made it possible to study the metabolism of even such complex and refractory connective tissues as bone. Using properly validated assays of enzyme activity in unfixed sections from various tissues a number of the diseases of the connective tissues have been studied. For example the synovia from patients with rheumatoid arthritis and related conditions have been studied using these techniques and marked alterations in the metabolism of the synovial lining cell population of this tissue have been demonstrated. These alterations in metabolism are believed to be related to the destruction of cartilage and bone found in such diseases. Investigations of the metabolism of the chondrocytes of articular cartilage in a strain of mice which spontaneously develops osteoarthritis has revealed a lack of certain key enzymes of carbohydrate metabolism in precisely those areas where degradation of the matrix of articular cartilage begins suggesting a causal relationship between these events. These same techniques have been used to study the cellular kinetics and metabolism of the dermis and epidermis in the disfiguring disease, psoriasis. The metabolism of healing bone fractures, the diagnosis and treatment of the mucopolysaccharidoses and the metabolic effects of currently used anti-inflammatory and anti-rheumatic drugs have also been examined. Perhaps the most exciting aspect of these studies has been the development and use of the technique of the cytochemical bioassay (CBA) to study hormonally mediated diseases of the connective tissues. Such studies have recently shed new light on the molecular lesion in pseudohypoparathyroidism. Though still in their relative infancy the studies described in this review show the potential inherent in the use of quantitative cytochemistry for the study of diseases of the connective tissues.

Topics: Animals; Arthritis, Rheumatoid; Cartilage, Articular; Cell Division; Connective Tissue Diseases; Disease Models, Animal; Epidermal Cells; Fractures, Bone; Glucosephosphate Dehydrogenase; Glycolysis; Hexosephosphates; Histocytochemistry; Humans; Lysosomes; Mitochondria; Mucopolysaccharidoses; NADP; Osteoarthritis; Pseudohypoparathyroidism; Psoriasis; Synovial Membrane; Vitamin K; Wound Healing; Zinc

Osteoarthritis (OA) is a progressive disease for which there is no disease modifying therapy. Vitamin K levels and vitamin K antagonism have been associated with risk and progression of OA which may have direct implications for clinical management, but these observational findings are susceptible to confounding. We aimed to estimate the causal association between vitamin K and OA risk using Mendelian randomisation (MR).. We used data from the largest genome-wide association study (GWAS) of OA to date (up to 826,690 individuals) to estimate the effect of genetically predicted vitamin K level (instrumented using four variants derived from a GWAS of 2,138 individuals) on risk of all OA types, knee, hip, spine, hand OA, and total joint replacement. We employed the inverse-variance weighted method for the primary analysis and, in a series of sensitivity analyses, adjusted for sub-genome wide significant instruments and tested for potential bias from pleiotropy.. We showed that genetically predicted vitamin K levels were not causally associated with risk of OA overall (OR 0.98 per unit increase in log-transformed vitamin K1; 95%CI 0.96-1.01), knee (OR 0.98; 0.92-1.03), hip (OR 0.97; 0.88-1.07), spine (OR 0.97; 0.90-1.04), hand OA (OR 0.97; 0.91-1.04) or joint replacement (OR 0.96; 0.89-1.04). Results were similar across all sensitivity analyses.. We found little evidence of a causal association between genetically predicted vitamin K and OA risk. Larger genetic and interventional studies of vitamin K are required to confirm our findings.

Topics: Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Osteoarthritis; Polymorphism, Single Nucleotide; Vitamin K

Topics: Humans; Osteoarthritis; Vitamin K

We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin.. Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1β; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes.. We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression.. Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in cartilage. The determined direct negative effect of warfarin on human explant cultures functionally underscores the previously found association between vitamin K deficiency and OA.

Topics: Alleles; Calcium-Binding Proteins; Cartilage, Articular; Cell Adhesion Molecules; Collagen Type I, alpha 1 Chain; Collagen Type X; Down-Regulation; Extracellular Matrix Proteins; Gene Expression; Humans; Matrix Gla Protein; Matrix Metalloproteinase 3; Osteoarthritis; RNA, Messenger; SOX9 Transcription Factor; Up-Regulation; Vitamin K; Warfarin

Identification of modifiable risk factors and treatments for osteoarthritis (OA) are needed. Warfarin, a vitamin K antagonist, causes fetal and animal model skeletal abnormalities. Vitamin K insufficiency has been associated with OA, but whether warfarin is also detrimental to OA is not known.. We conducted a nested case-control study using a UK general practitioner electronic medical records database. We identified cases of knee or hip replacement (KR or HR) from among adults with atrial fibrillation newly prescribed either warfarin or direct oral anticoagulants (DOACs). Cases were matched with four controls by age and sex. We assessed the relation of warfarin compared with DOAC use to risk of joint replacement using conditional logistic regression. We also evaluated different durations of warfarin use.. We identified 857 subjects with KR or HR (cases), of whom 64.6% were warfarin users, and 3428 matched controls, of whom 56.1% were warfarin users (mean age 75, 47% female). Warfarin users had a 1.59 times higher risk of joint replacement than DOAC users (adjusted OR 1.59, 95% CI 1.31 to 1.92). Longer duration of warfarin use was associated with higher risk of joint replacement in comparison with <1 year of warfarin use.. Warfarin, a vitamin K antagonist, was associated with greater risk of KR and HR (an indicator for end-stage knee OA) than DOAC use, supporting the importance of adequate vitamin K functioning in limiting OA progression.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Case-Control Studies; Databases, Factual; Female; Humans; Male; Middle Aged; Osteoarthritis; Risk Factors; Vitamin K; Warfarin

Vitamin K is hypothesised to play a role in osteoarthritis (OA) pathogenesis through effects on vitamin K-dependent bone and cartilage proteins, and therefore may represent a modifiable risk factor. A genetic variant in a vitamin K-dependent protein that is an essential inhibitor for cartilage calcification, matrix Gla protein (MGP), was associated with an increased risk for OA. Vitamin K antagonist anticoagulants (VKAs), such as warfarin and acenocoumarol, act as anticoagulants through inhibition of vitamin K-dependent blood coagulation proteins. VKAs likely also affect the functioning of other vitamin K-dependent proteins such as MGP.. We investigated the effect of acenocoumarol usage on progression and incidence of radiographic OA in 3494 participants of the Rotterdam Study cohort. We also examined the effect of. These findings support the importance of vitamin K and vitamin K-dependent proteins, as MGP, in the pathogenesis of OA. Additionally, these results may have direct implications for the clinical prevention of OA, supporting the consideration of direct oral anticoagulants in favour of VKAs.

Topics: 4-Hydroxycoumarins; Acenocoumarol; Aged; Alleles; Anticoagulants; Calcium-Binding Proteins; Disease Progression; Extracellular Matrix Proteins; Female; Humans; Incidence; Indenes; Male; Matrix Gla Protein; Middle Aged; Osteoarthritis; Polymorphism, Single Nucleotide; Prospective Studies; Vitamin K; Vitamin K Epoxide Reductases

Mineralization has been observed in osteoarthritic cartilage but the mechanisms are incompletely understood. Vitamin K is an essential cofactor in post-translational modification of proteins where specific Glu residues become modified to Ca(++) binding gamma-carboxyglutamic acid residues (Gla). One such protein, matrix Gla protein (MGP), is a known mineralization inhibitor. This study determined if synthesis of MGP and formation of a fetuin-MGP protein complex was altered in chondrocytes and vesicles from osteoarthritis (OA) cartilage.. Chondrocytes and vesicles were isolated from normal and OA human articular cartilage and lysates prepared. Specific antibodies were used in immunoblotting to detect the mature fully gamma-carboxylated form of MGP (cMGP) and non-gamma-carboxylated MGP (ucMGP) as well as fetuin and MGP-fetuin complexes. gamma-carboxylase activity was measured by (14)CO(2) incorporation into the carboxylase peptide substrate FLEEL. Immunocytochemistry was used to examine fetuin in cartilage sections and uptake of biotin-labeled fetuin by isolated chondrocytes.. Chondrocytes and vesicles from osteoarthritic tissue produced significantly less cMGP compared to those from normal cartilage. This correlated with significantly less vitamin K-dependent gamma-carboxylase enzyme activity in OA chondrocytes. Fetuin was found to be present in articular cartilage and cultured chondrocytes were capable of fetuin uptake. A fetuin-MGP complex was identified in normal chondrocytes and in vesicles shed from these cells but not in OA cells or vesicles.. The absence of cMGP and of the cMGP-fetuin complex in OA cells and OA vesicles may be an important mechanism for increased mineralization of osteoarthritic cartilage.

Topics: alpha-Fetoproteins; Calcium-Binding Proteins; Cartilage, Articular; Chondrocytes; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Osteoarthritis; Protein Processing, Post-Translational; Vitamin K

Topics: Aged; Anticoagulants; Arthritis, Rheumatoid; Arthroplasty; Aspirin; Blood Coagulation; Blood Platelets; Dextrans; Follow-Up Studies; Heparin; Hip Joint; Humans; Joint Prosthesis; Osteoarthritis; Postoperative Complications; Spondylitis, Ankylosing; Vitamin K; Warfarin

Topics: Back Pain; Chondroitin; Glucuronates; Humans; Low Back Pain; Osteoarthritis; Osteoporosis; Prednisolone; Spinal Diseases; Spinal Dysraphism; Tuberculosis; Tuberculosis, Spinal; Vitamin K