osteoprotegerin and Osteoarthritis--Knee

Although the osteoprotegerin (OPG)/RANK/RANKL system is the main modulator of bone remodeling, it remains unclear whether it is regulated in cartilage during osteoarthritis (OA). The aim of this study was to examine whether nonsteroidal antiinflammatory drug (NSAID) treatment modulates the synthesis of OPG and RANKL in the cartilage of patients with OA, and to investigate whether prostaglandin E(2) (PGE(2)) modifies this system in human OA chondrocytes in culture.. A 3-month clinical trial was carried out in 20 patients with severe knee OA, all of whom were scheduled to undergo knee replacement surgery. Ten of these patients were treated with celecoxib, and the other 10 patients, who did not want to be treated, served as the control group. After surgery, cartilage was processed for molecular biology studies. We also used human OA chondrocytes to examine the effects of PGE(2) on OPG/RANKL synthesis, examining which surface receptors were affected by PGE(2).. In patients with OA, celecoxib decreased RANKL synthesis in the cartilage, thereby increasing the OPG:RANKL ratio. In human OA chondrocytes in culture, PGE(2) elicited a dose- and time-dependent increase in the synthesis of RANKL, the extent of which was greater than that of OPG. Confocal microscopy revealed that PGE(2) induced RANKL transport to the cell membrane. Only EP2/EP4 agonists reproduced the effects of PGE(2) on OPG and RANKL induction.. Long-term NSAID treatment inhibited the resorptive signal synthesized by chondrocytes. In vitro, PGE(2) regulated the expression and release of these key mediators of bone metabolism by articular chondrocytes. The role of OPG/RANK/RANKL in OA cartilage metabolism is still unknown, although the synthesis of these proteins would enable the cartilage to control the activity of subchondral bone cells.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cells, Cultured; Chondrocytes; Cyclooxygenase 2 Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Gene Expression; Humans; Immunohistochemistry; Osteoarthritis, Knee; Osteoprotegerin; Pyrazoles; RANK Ligand; Receptors, Prostaglandin E; Severity of Illness Index; Signal Transduction; Sulfonamides

To investigate the effects of acupotomy on inhibiting abnormal formation of subchondral bone in rabbits with knee osteoarthritis (KOA).. A total of 24 New Zealand rabbits were randomly divided into four groups of 6 rabbits each [control, model, electroacupuncture (EA) and acupotomy]. Eighteen KOA model rabbits were established using a modified Videman method. Rabbits in EA and acupotomy groups received the intervention for 3 weeks. Then, the cartilage and subchondral bone unit were obtained and the histomorphological changes were recorded. Osteo-protegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) in subchondral bone were evaluated by Western blotting, real-time polymerase chain reaction and immunohistochemistry.. Compared with the model group, both the acupotomy and EA groups showed a significant decrease in the Lequesne index (both 0.01) and Mankin score ( 0.01, < 0.05). In addition, both EA and acupotomy groups had a higher expression of total articular cartilage (TAC) ( 0.05, < 0.01) and lower expression of articular calcified cartilage (ACC)/TAC ( 0.05, < 0.05) compared with the model group. The thickness of the subchondral bone plate in EA and acupotomy groups were decreased (both 0.01) compared to the model group. Moreover, trabecular bone volume (BV/TV), protein and relative expression of OPG and the ratio of OPG/RANKL in the subchondral bone of acupotomy group were decreased statistically significant, while these parameters were not significantly changed in the EA group compared with the model group.. In the rabbit model of KOA, acupotomy inhibits aberrant formation of subchondral bone by suppressing OPG/RANKL ratio as a potential therapy for KOA.

Topics: Acupuncture Therapy; Animals; Cartilage, Articular; Humans; Osteoarthritis, Knee; Osteoprotegerin; Rabbits; RANK Ligand

To investigate the effect of internal heat-type acupuncture needle on the expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), and receptor activator of NF-κB (RANK) in knee osteoarthritis (KOA) rabbits, so as to explore its mechanisms in relieving KOA.. Thirty New Zealand rabbits were randomly divided into control, model and treatment groups, with 10 rabbits in each group. The KOA model was established by using Hulth method. The rabbits of the treatment group received internal heat-type acupuncture needles (42 ℃) on the left hind limb 20 min, once a week for 4 weeks. The behavioral scores were assessed according to the pain severity, gait, joint motion range and articular swelling severity in reference to the modified Lequesne's methods. Toluidine Blue staining was performed to observe the structure of the subchondral bone and to analyze the difference of morphometric parameters. The protein and mRNA expressions of OPG, RANKL and RANK were detected by Western blot and real-time PCR, respectively.. Compared with the control group, the Lequesne total score, the separation degree of trabecular bone, the protein and mRNA expressions of RANKL and RANK in subchondral bone tissues were significantly increased in the model group, while the percentage of trabecular bone area, number of trabecular bone, the expression of OPG protein and mRNA were decreased (. The internal heat-type acupuncture needle therapy can improve the motor function of rabbits with KOA, which may be related to its effects in up-regulating the expression of OPG and down-regulating the RANKL and RANK in subchondral bone tissue.

Topics: Acupuncture Therapy; Animals; Bone and Bones; Hot Temperature; Ligands; Needles; Osteoarthritis, Knee; Osteoprotegerin; Rabbits; Receptor Activator of Nuclear Factor-kappa B

In rats with modeled posttraumatic knee osteoarthrosis, negative changes in subchondral bone metabolism were revealed: a tendency to an increase in osteocalcin concentration, a decrease in sclerostin and osteoprotegerin levels, and a significant increase in FGF-23 concentration accompanied by a slight elevation of inorganic phosphorous and significant increase in total calcium levels in comparison with the corresponding parameters in intact controls. These findings demonstrate crucial importance of structural integrity of the subchondral bone, because its protection improves the results of reconstructive therapy for local cartilage defects.

Topics: Animals; Animals, Outbred Strains; Bone and Bones; Calcium; Cartilage, Articular; Disease Models, Animal; Knee Injuries; Knee Joint; Male; Osteoarthritis, Knee; Osteocalcin; Osteoprotegerin; Phosphorus; Rats

It was a cross-sectional study where 80 (43 women and 37 men) newly diagnosed subjects with OA knee were recruited. They were classified into four grades based on K-L grading and into two groups as early (grade 1+grade 2) and advanced (grade 3 + grade 4) based on the disease progression.. On comparing the biochemical parameters among the four grades decreasing vitamin D levels were seen with increasing severity of knee OA; an increasing trend of RANKL with increase in the severity of OA was seen; OPG was found to be elevated more in the early stages of OA. We also observed a strong association of RANKL/OPG ratio with disease severity.. Overall the results suggest that OPG may be considered as an early marker of the diseases.

Topics: Cross-Sectional Studies; Female; Humans; Ligands; Male; Osteoarthritis, Knee; Osteoprotegerin; RANK Ligand; Vitamin D; Vitamins

Previous studies have shown that Tougu Xiaotong capsule (TGXTC) has therapeutic effects on knee osteoarthritis (OA) through multiple targets. However, the mechanisms of action underlying its regulation of subchondral bone reconstruction remain unclear. In this study, we investigated the effects of TGXTC on subchondral bone remodeling. Eighteen six-month-old New Zealand white rabbits of average sex were randomly divided into the normal, model and TGXTC groups. The rabbit knee OA model was induced by a modified Hulth's method in the model and TGXTC groups, but not the normal group. Five weeks postoperatively, intragastric administration of TGXTC was performed for four weeks. After drug administration, the medial femoral condyle and tibia were prepared for observation of cartilage histology via optical microscopy and micro-computed tomography, the serum was collected for biochemical parameters assay and the subchondral bone isolated from the lateral femoral condyle was collected for detection of IL-1β and TNF-α mRNA and protein by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The results showed that treatment with TGXTC significantly mitigated cartilage injury and subchondral bone damage, improved the parameter of subchondral trabecular bone, decreased alkaline phosphatase and tartrate-resistant acid phosphatase activity, and significantly reducing the osteoprotegerin/receptor activator of nuclear factor-κB ligand ratio, reduced the expression of IL-1β and TNF-α mRNA and protein. These results suggest that TGXTC could delay the pathological development of OA by regulating subchondral bone remodeling through regulation of bone formation and bone resorption and its relating inflammatory factors, and this may partly explain its clinical efficacy in the treatment of knee OA.

Topics: Alkaline Phosphatase; Animals; Bone Remodeling; Cancellous Bone; Cartilage, Articular; Drugs, Chinese Herbal; Female; Interleukin-1beta; Osteoarthritis, Knee; Osteoprotegerin; Rabbits; RANK Ligand; RNA, Messenger; Tartrate-Resistant Acid Phosphatase; Tumor Necrosis Factor-alpha; X-Ray Microtomography

Osteoarthritis (OA) is usually recognized to have a genetic factor, and in our study, we performed a case-control study to analyze the association between 14 single nucleotide polymorphisms (SNPs) in OPG and the risk of knee OA in a Chinese Han population.. Fourteen OPG SNPs were assayed using MassARRAY in 393 patients clinically and radiographically diagnosed with knee OA and in 500 controls. Allelic and genotypic frequencies were compared between the groups. Logistic regression adjusting for age and gender was used to estimate risk associations between specific genotypes and knee OA by computing odds ratios (ORs) and 95% confidence intervals (95% CIs).. We found that the minor alleles of six SNPs in OPG were associated with an increased or decreased risk of knee OA in the allelic model analysis. In the genetic model analysis, we found that rs1905786, rs1032128, rs3134058, rs11573828, rs11573849, rs3134056, and rs1564861 were associated with an increased or decreased risk of knee OA before adjusted by sex and age. And after adjustment, three SNPs (rs1485286, rs1905786, and rs1032128) were identified to have a negative effect on knee OA.. Our results verify that genetic variants of OPG contribute to knee OA susceptibility in the population of northern China. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

Topics: Aged; Alleles; Asian People; Case-Control Studies; China; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Odds Ratio; Osteoarthritis, Knee; Osteoprotegerin; Polymorphism, Single Nucleotide; Risk Factors

Knee osteoarthritis (KOA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Several inflammatory markers and cartilage degradation products can be used as biomarkers in OA. The key factors of bone metabolism in normal joint bone, dickkopf-1 (DKK1) and osteoprotegerin (OPG), interact with Wnt signaling pathway, balancing between bone absorption and bone reconstruction. TNF-α is a key inducer of DKK-1, which belongs to the family of proteins involved in joint remodeling. The present study compared the serum levels of DKK1, TNF-α, and OPG in patients with KOA and healthy controls to analyze the interrelationship and the severity of joint destruction. One hundred forty-eight patients with KOA and 101 healthy controls were enrolled in this study. Anteroposterior knee radiographs determined the severity of the disease in the affected knee. The radiographic grading of KOA was performed by the Kellgren-Lawrence criteria. Serum levels of DKK-1, TNF-α, and OPG were estimated using the multiplex particle-based flow cytometry. Higher serum levels of OPG and TNF-α were observed in KOA than the controls; KOA patients showed a lower serum level of DKK-1, whereas the serum levels of DKK1 correlated with the progression of KOA. The serum levels of TNF-α, OPG, and DKK-1 correlated with incident KOA. In the ROC curve analysis, DKK1 levels showed 78.6% sensitivity and 40% specificity, TNF-α levels showed 74.1% sensitivity and 76.0% specificity, and OPG showed 88.1% sensitivity and 81% specificity in predicting severe KOA. In the univariate and multivariate analyses, TNF-α and OPG emerged as independent predictors of severe KOA. This study, for the first time, combined TNF-α, DKK1, and OPG as valuable biological markers in predicting the severity of KOA radiographically in the clinic. This study also supported the inflammation-induced DKK1 and OPG in OA pathogenesis.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone and Bones; Bone Remodeling; Case-Control Studies; Disease Progression; Female; Flow Cytometry; Gene Expression Regulation; Humans; Incidence; Intercellular Signaling Peptides and Proteins; Male; Middle Aged; Multivariate Analysis; Osteoarthritis, Knee; Osteoprotegerin; Sensitivity and Specificity; Severity of Illness Index; Signal Transduction; Tumor Necrosis Factor-alpha

Osteoarthritis is the most common chronic joint disorder especially during aging. Although with controversies, glucosamine, both in its forms of sulfate and hydrochloride, and chondroitin sulfate are commonly employed to treat osteoarthritis. Due to the modest improve in the symptoms observed in patients treated with these drugs alone, a formulation combining both agents has been considered. The discrepant results achieved for pain control or structural improvement in osteoarthritis patients has been attributed to the quality of chemical formulations or different bias in clinical studies. The current study has been designed to test the effects of two different combined formulations with adequate pharmaceutical grade of these drugs in osteoarthritic joints, and to explore the underlying mechanisms modulated by both formulations in different osteoarthritis target tissues. Knee osteoarthritis was surgically induced in experimental rabbits. Some animals received the combined therapy (CT)1, (chondroitin sulfate 1200mg/day + glucosamine sulfate 1500mg/day), or the CT2 ((chondroitin sulfate 1200mg/day + glucosamine hydrochloride 1500mg/day). Neither CT1 nor CT2 significantly modified the cartilage damage or the synovial inflammation observed in osteoarthritic animals. Treatments were also unable to modify the presence of pro-inflammatory mediators, and the synthesis of metalloproteinases in the cartilage or in the synovium of osteoarthritic animals. Combined therapies did not modify the decrease in the subchondral bone mineral density observed in osteoarthritic rabbits. Therapies of chondroitin sulfate plus glucosamine sulfate or chondroitin sulfate plus glucosamine hydrochloride failed to improve structural damage or to ameliorate the inflammatory profile of joint tissues during experimental osteoarthritis.

Topics: Animals; Bone Density; Cartilage, Articular; Chondroitin Sulfates; Cytokines; Disease Models, Animal; Drug Interactions; Glucosamine; Knee Joint; Male; Matrix Metalloproteinases; Osteoarthritis, Knee; Osteoprotegerin; Rabbits; RANK Ligand; Synovial Membrane

Osteoarthritis (OA) is a common cause of functional deterioration in older adults, and altered chondrogenesis is the most common pathophysiological process involved in the development of OA. MicroRNA‑145 (miR‑145) has been shown to regulate chondrocyte homeostasis. However, the function of miR‑145 in OA remains to be elucidated. In the present study, the expression levels of miR‑145 were examined in cartilage specimens from 25 patients with knee OA using reverse transcription‑quantitative polymerase chain reaction analysis. The effects of miR‑145 on the proliferation and fibrosis of the C‑20/A4 and CH8 cell lines were also investigated using 3-(4,5-dimethylth-iazol-2-yl)-2,5-diphenyltetrazolium bromide and western blot assays in vitro. The results revealed that the expression of miR-145 was decreased in the OA cartilage tissues, compared with normal cartilage tissues. The overexpression of miR‑145 by transfection of cells with miR‑145 mimics significantly inhibited C‑20/A4 and CH8 cell proliferation and fibrosis. Furthermore, tumor necrosis factor receptor superfamily, member 11b (TNFRSF11B) was identified as a direct target of miR‑145 in chondrocytes, which was confirmed using a dual‑luciferase reporter assay. The expression level of TNFRSF11B was markedly upregulated in the patients with OA, and the ectopic expression of miR‑145 was capable of suppressing the expression of TNFRSF11B. In addition, the knock down of TNFRSF11B using specific small interfering RNA also inhibited the proliferation and fibrosis of C‑20/A4 and CH8 cells in vitro. These data provide the first evidence, to the best of our knowledge, to suggest the critical function of miR‑145 in regulating the expression of TNFRSF11B, which may have important implications on the regulation of chondrocyte proliferation and fibrosis in OA.

Topics: Cartilage, Articular; Cell Line; Cell Proliferation; Chondrocytes; Fibrosis; Gene Expression Regulation; Humans; MicroRNAs; Osteoarthritis, Knee; Osteoprotegerin

The imbalance of subchondral bone remodeling is a common pathological feature in the progression of osteoarthritis. In the current study, using a rabbit model of knee osteoarthritis, the effects of the Tougu Xiaotong capsule (TGXTC) on the cartilage and subchondral bone were investigated. In addition, osteoprotegerin (OPG), an inducer of bone formation, and receptor activator of nuclear factor‑κB ligand (RANKL), a regulator of bone resorption in the subchondral bone, were assessed, in order to further explore the protective role of TGXTC in subchondral bone remodeling. The rabbit model of knee osteoarthritis, which was induced by a modified version of Hulth's method, was treated with TGXTC or glucosamine hydrochloride for 4 or 8 weeks. Subsequently, the tibia and femur were harvested for observation of cartilage histology, and the subchondral bone was observed by scanning electron microscopy. The expression levels of OPG and RANKL at the gene and protein levels were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. TGXTC and glucosamine hydrochloride were identified to mitigate cartilage injury, reduce trabecular number and thickness and accelerate trabecular separation. It was additionally observed that the level of OPG mRNA and protein expression was reduced, and the RANKL mRNA and protein expression level was increased, in addition to the observation of a lower OPG/RANKL ratio in the TGXTC and hydrochloride groups. Taken together, these results suggest that TGXTC may mitigate cartilage injury and subchondral sclerosis, thus delaying the pathological development of osteoarthritis. This is suggested to be mediated partly through the reduction of OPG expression and increase of RANKL expression, which reduces the OPG/RANKL ratio, suppressing excessive bone formation.

Topics: Animals; Capsules; Cartilage; Drugs, Chinese Herbal; Female; Femur; Osteoarthritis, Knee; Osteoprotegerin; Protective Agents; Rabbits; RANK Ligand; RNA, Messenger

Recent data have shown that abnormal subchondral bone remodeling plays an important role in osteoarthritis (OA) onset and progression, and it was suggested that abnormal mechanical pressure applied to the articulation was responsible for these metabolic changes. This study was undertaken to evaluate the effects of cyclic compression on osteoblasts from OA subchondral bone.. Osteoblasts were isolated from sclerotic and nonsclerotic areas of human OA subchondral bone. After 28 days, the osteoblasts were surrounded by an abundant extracellular matrix and formed a resistant membrane, which was submitted to cyclic compression (1 MPa at 1 Hz) for 4 hours. Gene expression was evaluated by reverse transcription-polymerase chain reaction. Protein production in culture supernatants was quantified by enzyme-linked immunosorbent assay or visualized by immunohistochemistry.. Compression increased the expression of genes coding for interleukin-6 (IL-6), cyclooxygenase 2, RANKL, fibroblast growth factor 2, IL-8, matrix metalloproteinase 3 (MMP-3), MMP-9, and MMP-13 but reduced the expression of osteoprotegerin in osteoblasts in both sclerotic and nonsclerotic areas. Colα1(I) and MMP-2 were not significantly affected by mechanical stimuli. Nonsclerotic osteoblasts were significantly more sensitive to compression than sclerotic ones, but after compression, differences in messenger RNA levels between nonsclerotic and sclerotic osteoblasts were largely reduced or even abolished. Under basal conditions, sclerotic osteoblasts expressed similar levels of α5, αv, β1, and β3 integrins and CD44 as nonsclerotic osteoblasts but 30% less connexin 43, an important mechanoreceptor.. Genes involved in subchondral bone sclerosis are mechanosensitive. After compression, nonsclerotic and sclerotic osteoblasts expressed a similar phenotype, suggesting that compression could be responsible for the phenotype changes in OA subchondral osteoblasts.

Topics: Aged; Bone and Bones; Bone Remodeling; Cyclooxygenase 2; Fibroblast Growth Factor 2; Humans; Interleukins; Matrix Metalloproteinases; Osteoarthritis, Knee; Osteoblasts; Osteoprotegerin; RANK Ligand; Stress, Physiological

We examined single-nucleotide polymorphisms (SNPs) across the tumour necrosis factor receptor superfamily member 11B (TNFRSF11B) gene and knee OA. We identified alleles in a VNTR region in intron 3 that was observed exclusively in women OA cases (P = 0.007, Pc = 0.042). Our results reveal that a previously unreported association between a VNTR genotype in TNFRSF11B and knee OA in women.

Topics: Alleles; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Minisatellite Repeats; Osteoarthritis, Knee; Osteoprotegerin; Polymorphism, Single Nucleotide; Sex Factors

Hemarthrosis triggers hemophilic arthropathy, involving the target joints. The histopathogenesis of blood-induced joint damage remains unclear. The triad of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG; RANK-RANKL-OPG) controls bone turnover. Our aim was to evaluate RANK-RANKL-OPG expression in the synovium of hemophilic patients with severe arthropathy.. Synovial biopsies were obtained from 18 patients with hemophilic arthropathy and 16 with osteoarthritis (OA) who were undergoing total knee replacement and synovectomy. The severity of hemophilic arthropathy was evaluated according to ultrasonography score, the World Federation of Hemophilia (WFH) orthopedic joint scale, and the radiographic Pettersson score. RANK-RANKL-OPG expression was examined by immunohistochemistry and Western blotting. Serum levels of soluble RANKL (sRANKL) and OPG from an extended group of 67 patients with hemophilic arthropathy and 30 healthy controls were measured by ELISA.. The mean ultrasonography, WFH orthopedic joint scale, and Pettersson scores in patients with hemophilic arthropathy indicated severe arthropathy. A decreased expression of OPG was found in hemophilic arthropathy synovium compared with patients with OA. RANK and RANKL immunopositivity was strong in the lining and sublining layers in hemophilic arthropathy synovial tissue. Western blotting confirmed the immunohistological findings. Serum levels of sRANKL and OPG in patients with hemophilia were lower than in healthy controls.. In hemophilic arthropathy, the synovium highly expressed RANK and RANKL, whereas OPG immunopositivity decreased, suggesting an osteoclastic activation. Low tissue expression of OPG paralleled the serum levels of this protein and the severity of hemophilic arthropathy assessed by ultrasonography, Pettersson, and WFH orthopedic joint scale scores.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Female; Hemarthrosis; Humans; Knee Joint; Male; Middle Aged; Osteoarthritis, Knee; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Severity of Illness Index; Signal Transduction; Synovial Membrane; Ultrasonography

Blunt trauma of articular cartilage, often resulting from accidents or sports injuries, is associated with local inflammatory reactions and represents a major risk factor for development of post-traumatic osteoarthritis. TNF-α is increased in synovial fluid early after trauma, potentiates injury-induced proteoglycan degradation and may act proapoptotic under permissive conditions. We asked whether TNF-α also influences chondrocyte death, gene expression of catabolic and anabolic markers and the release of proinflammatory mediators in the early post-traumatic phase. Interactive effects of a defined single impact trauma (0.59 J) and TNF-α (100 ng/ml) on human early-stage osteoarthritic cartilage were investigated in vitro over 24 h. Exposure of traumatized cartilage to TNF-α did not increase chondrocyte death. IL-6-synthesis was augmented by trauma, TNF-α and combined treatment. The impact increased the release of PGE2 and PGD2 in the presence and absence of TNF-α to a similar extent while TNF-α alone showed no effect. In contrast, NOS2A-expression and nitric oxide (NO)-release were not affected by trauma but significantly increased by TNF-α. Expression of OPG and RANKL was not affected by TNF-α but modulated by trauma. TNF-α with and without trauma significantly induced MMP1 gene expression. These results indicate that TNF-α does not potentiate early cell death in early-stage osteoarthritic cartilage after blunt injury. However, trauma and TNF-α showed independent and interactive effects concerning prostaglandin and NO release. TNF-α probably contributes to cartilage degradation after trauma by an early induction of MMP1 gene expression. Our study confirms that an anti-TNF-α therapy may have inhibitory effects on catabolic and, partly, on inflammatory processes after a single impact trauma. As TNF-α does not contribute to the loss of chondrocytes in the initial post-traumatic phase, a combination with pharmaco-therapeutic strategies reducing early cell death could be reasonable.

Topics: Aged; Apoptosis; Cartilage, Articular; Cell Survival; Chondrocytes; Cyclooxygenase 2; Dinoprostone; Gene Expression; Humans; Interleukin-6; Intramolecular Oxidoreductases; Lipocalins; Matrix Metalloproteinase 1; Middle Aged; Nitrates; Nitric Oxide Synthase Type II; Osteoarthritis, Knee; Osteoprotegerin; Prostaglandin D2; Prostaglandin-E Synthases; RANK Ligand; Tissue Culture Techniques; Tumor Necrosis Factor-alpha

Determination of the serum levels of Receptor Activator of Nuclear Factor-Κb Ligand, bone-specific alkaline phosphatase, osteocalcin and osteoprotegerin in patients suffering from osteoarthritis of varying severity and healthy controls and correlation of these results with the patients' age and the radiographically assessed severity of the disease.. Patients suffering from hip (n=58) or knee (n=117) osteoarthritis and matched controls (n=19) were enrolled in this study. Patients underwent physical examination and standard radiographic evaluation before blood sampling.. The serum levels of osteoprotegerin were positively correlated with age in all groups, whereas those of osteocalcin in the 'knee' group only. Osteoarthritis' severity and location did not have a statistically significant impact on the mean serum level of any marker in both groups.. Based on our results, none of the studied markers can serve as a surrogate for radiographic imaging in patients suffering from hip and knee osteoarthritis.

Topics: Alkaline Phosphatase; Humans; Osteoarthritis, Knee; Osteocalcin; Osteoprotegerin; RANK Ligand

TSG-6 (the product of tumor necrosis factor [TNF]-stimulated gene 6) has a potent inhibitory effect on RANKL-mediated bone erosion. The aim of this study was to compare the activity of TSG-6 with that of osteoprotegerin (OPG) and to investigate its role as an autocrine modulator of cytokine-mediated osteoclast formation/activation. We also determined TSG-6 expression in inflammatory joint disease.. The effects of TSG-6, OPG, and the inflammation mediators TNFα, interleukin-1 (IL-1), and IL-6 on the formation of osteoclasts from peripheral blood mononuclear cells and synovial fluid (SF) macrophages were determined by tartrate-resistant acid phosphatase staining. Lacunar resorption and filamentous actin ring formation were measured as indicators of osteoclast activity. The amount of TSG-6 in culture media or SF was quantified by enzyme-linked immunosorbent assay, and expression of TSG-6 in synovial tissue was assessed by immunohistochemistry.. TSG-6 acted in synergy with OPG to inhibit RANKL-mediated bone resorption and was produced by osteoclast precursors and mature osteoclasts in response to TNFα, IL-1, and IL-6. Expression of TSG-6 correlated with inhibition of lacunar resorption; this effect was ameliorated by an anti-TSG-6 antibody. The level of TSG-6 protein was determined in SF from patients with various arthritides; it was highest in patients with inflammatory conditions such as rheumatoid arthritis, in which it correlated with the amount of TSG-6 immunostaining in the synovium. TSG-6 inhibited the activation but not the formation of osteoclasts from SF macrophages.. In the presence of inflammatory cytokines, osteoclasts produced TSG-6 at concentrations that are sufficient to inhibit lacunar resorption. This may represent an autocrine mechanism to limit the degree of bone erosion during joint inflammation.

Topics: Aged; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autocrine Communication; Bone Resorption; Cell Adhesion Molecules; Cell Differentiation; Cells, Cultured; Female; Humans; Interleukin-1; Interleukin-6; Macrophages; Male; Osteoarthritis, Knee; Osteoclasts; Osteoprotegerin; Tumor Necrosis Factor-alpha

Impairment of subchondral bone density and quality aggravates cartilage damage in osteoarthritis (OA). Accordingly, we assessed whether improving microstructure and quality at subchondral bone by the bone-forming agent parathyroid hormone (PTH) [1-34] prevent cartilage damage progression in a rabbit model of OA preceded by osteoporosis (OP).. OP was induced in 20 female rabbits. At week 7, these rabbits underwent knee surgery to induce OA and, at week 12, they started either saline vehicle (n=10) or PTH (n=10) for 10 weeks. Ten healthy animals were used as controls. At week 22, microstructure was assessed by micro-computed tomography and bone remodelling by protein expression of alkaline phosphatase (ALP), metalloproteinase-9 (MMP9), osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) at subchondral bone. Cartilage damage was evaluated using Mankin score.. PTH reversed the decrease of bone area/tissue area, trabecular thickness, plate thickness, polar moment of inertia, ALP expression and OPG/RANKL ratio, as well as counteracted the increase of fractal dimension and MMP9 expression at subchondral bone of osteoarthritis preceded by osteoporosis (OPOA) rabbits compared to vehicle administration (P<0.05). Likewise, PTH decreased cartilage damage severity in OPOA rabbits. Good correlations were observed between subchondral bone structure or remodelling parameters, and cartilage Mankin score.. Improvement of microstructural and remodelling parameters at subchondral bone by PTH [1-34] contributed to prevent cartilage damage progression in rabbits with early OPOA. These findings support the role of subchondral bone in OA. Further studies are warranted to establish the place of bone-forming agents as potential treatment in OA.

Topics: Alkaline Phosphatase; Animals; Bone Remodeling; Cartilage, Articular; Case-Control Studies; Disease Models, Animal; Disease Progression; Female; Hindlimb; Matrix Metalloproteinase 9; Osteoarthritis, Knee; Osteoporosis; Osteoprotegerin; Parathyroid Hormone; Rabbits; RANK Ligand; X-Ray Microtomography

Interleukin-32 (IL-32) induces various inflammatory molecules in human monocytes and differentiation of monocytes into macrophage-like cells. This study was undertaken to evaluate the effects of IL-32gamma, the most biologically active isoform, on the differentiation and activation of osteoclasts.. CD14+ monocytes were obtained from healthy volunteers, and samples of synovial tissue and synovial fluid were obtained from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA). The concentration and expression levels of IL-32gamma in RA and OA samples were evaluated by enzyme-linked immunosorbent assay and immunoblotting, respectively. To examine the osteoclastogenic effects and functional activities, isolated monocytes were treated with either IL-32gamma or IL-17 in the presence or absence of soluble RANKL (sRANKL) on a culture system and on Osteologic disks. The expression of RANKL and osteoprotegerin (OPG) messenger RNA (mRNA) in RA fibroblast-like synoviocytes (FLS) was measured using reverse transcription-polymerase chain reaction (PCR) and real-time PCR.. The concentration and expression levels of IL-32gamma were higher in the RA samples than in the OA samples. Upon costimulation with sRANKL, the osteoclast count and resorbed area increased more significantly in the IL-32gamma-stimulated cultures than in those stimulated with IL-17. In the IL-32gamma-treated group without sRANKL stimulation, osteoclasts were differentiated, but the cells displayed low resorption activity. In RA FLS, RANKL mRNA expression increased in the presence of both IL-32gamma and IL-17. However, transcription of OPG decreased following IL-32gamma stimulation, resulting in a significant increase in the RANKL:OPG ratio.. Our results suggest that IL-32gamma is a potent mediator of active osteoclast generation in the presence of sRANKL. Moreover, this novel cytokine creates more favorable conditions for osteoclastogenesis in the RA joint by increasing the RANKL:OPG ratio in FLS.

Topics: Bone Resorption; Cathepsin K; Cell Differentiation; Cells, Cultured; Humans; Interleukins; Isomerism; Lipopolysaccharide Receptors; Monocytes; NFATC Transcription Factors; Osteoarthritis, Knee; Osteoclasts; Osteoprotegerin; Proto-Oncogene Proteins pp60(c-src); RANK Ligand; RNA, Messenger; Synovial Fluid; TNF Receptor-Associated Factor 6

A failure of total hip or knee artroplasty is associated with an increased production of joint fluid. This contains wear particles and host cells and proteins, and is assumed to be involved in the pathogenesis of aseptic loosening and periprosthetic osteolysis. This study investigated the effect of synovial fluid from patients with aseptically failed joint prostheses on osteoblast cultures.. Synovial fluid samples were obtained from patients with failed total joint prostheses (TJP; n=36) and from control patient groups (n = 16) involving cases without TJP and osteoarthritis, without TJP but with osteoarthritis, and with stable TJP. The samples were treated in the standard manner and then cultured with the SaOS-2 cell line which shows the characteristics and behaviour of osteoblasts. Each fluid sample was also examined for the content of proteins, cells and selected cytokines (IL-1ß, TNF-α, IL-6, RANKL and OPG detected by ELISA). We tested the hypothesis assuming that the fluids from failed joints would show higher cytotoxicity to osteoblast culture and we also expected higher levels of IL-1ß, TNF-α, IL-6, and RANKL in patients with TJP failure and/ or with more severe bone loss. The statistical methods used included the Kruskal-Wallis ANOVA and Mann-Whitney U test.. The fluids from failed TJPs showed the highest RANKL and the lowest OPG levels resulting in the highest RANKL/OPG ratio. However, there was no evidence suggesting that the joint fluids from failed TJPs would be more toxic to osteoblast culture than the fluids from control groups. In addition, no correlation was found between the fluid levels of molecules promoting inflammation and osteoclastic activity and the extent of bone loss in the hip (in terms of Saleh's classification) or the knee (AORI classification). In fact, the fluids from failed TJPs had higher protein levels in comparison with the controls, but the difference was not significant.. The finding of high RANKL levels and low OPG concentrations is in agreement with the theory of aseptic loosening and periprosthetic osteolysis. The other cytokines, particularly TNF-α and IL-1ß, were found in low levels. This can be explained by the stage of particle disease at which the samples were taken for ELISA analysis. It is probable that the level of signal molecules reflects osteolytic process activity and is therefore not constant. The reason for no correlation found between cytokine levels and the extent of bone loss may also lie in the use of therapeutic classifications of bone defects that is apparently less sensitive to the biological activity of aseptic loosening and/or periprosthetic osteolysis.. Synovial fluids from failed total hip or knee joint prostheses are not toxic to osteoblast cultures. Cytotoxicity indicators and levels of pro-inflammatory and pro-osteoclastic cytokines (IL-1ß, TNF-α, IL-6, RANKL and OPG) do not correlate well with the extent of periprosthetic bone loss. Key words: total joint replacement, arthroplasty, aseptic loosening, periprosthetic osteolysis, joint fluid, SaOS-2 cell line, cytotoxicity, cytokines, RANKL, OPG.

Topics: Aged; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Cells, Cultured; Female; Humans; Interleukin-6; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteoblasts; Osteoprotegerin; Prosthesis Failure; RANK Ligand; Synovial Fluid; Tumor Necrosis Factor-alpha

To evaluate changes in serum levels of bone turnover markers during the first year following a total hip or knee arthroplasty (THA or TKA, respectively).. 34 women and 13 men (mean age, 68 years) with idiopathic hip or knee osteoarthritis underwent elective THA or TKA. The serum levels of (1) osteoprotegerin, (2) nuclear factor-kappa B ligand (RANKL), (3) osteocalcin, and (4) bone-specific alkaline phosphatase (b-ALP) were determined in each patient on preoperative day 1 and postoperative day 3 and 7, and month 2, 4, 6, 8, 10, and 12.. All 4 markers changed significantly over the 12-month period. At month 12, values of all markers did not return to their preoperative levels uniformly. At month 8, the serum levels of osteoprotegerin, osteocalcin, and b-ALP remained higher than their respective preoperative values. The serum levels of RANKL gradually decreased after month 2, rendering this marker a potential index for fixation.. Bone turnover markers change following arthroplasties. Postoperative month 8 seems to be a milestone in the normal course of these markers.

Topics: Aged; Alkaline Phosphatase; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Biomarkers; Bone Remodeling; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osteoarthritis, Hip; Osteoarthritis, Knee; Osteocalcin; Osteoprotegerin; RANK Ligand; Time Factors

Earlier studies suggest the involvement of osteoprotegerin (OPG), RANK and RANK ligand (RANKL) in OA subchondral bone metabolism; however, few studies have looked at their functional consequences on chondrocytes. We compared the expression/production of OPG, RANK and RANKL on human normal and OA chondrocytes, and evaluated, on OA chondrocytes, their modulation by some catabolic factors. Furthermore, the role of OPG and RANKL on the production of catabolic/anabolic factors was assessed.. Expression was determined using real-time PCR, production of RANK and RANKL by flow cytometry and that of OPG by ELISA. Modulation of these factors was determined upon treatment with IL-1beta, TNF-alpha and PGE(2). The functional consequences were examined following treatment with soluble RANKL or OPG-Fc (OPG without the heparin-binding domain).. OPG, RANK and RANKL were expressed and produced by human chondrocytes. Membranous RANK was produced only by an OA chondrocyte subpopulation (29%) localized throughout the cartilage. The OPG/RANKL ratio was significantly (P = 0.05) reduced on the OA chondrocytes, whereas the RANK/RANKL ratio was significantly (P < 0.03) increased. OPG and membranous RANKL levels were significantly enhanced by IL-1beta, TNF-alpha and PGE(2), whereas membranous RANK was significantly increased only with IL-1beta. Administration of soluble RANKL had no effect on the OA chondrocytes. However, addition of OPG-Fc significantly stimulated MMP-13 (P = 0.05) and protease-activated receptor-2 (PAR-2) (P < 0.04) production.. Our findings showed that human chondrocytes express and produce OPG, RANK and RANKL. OA chondrocyte treatment with catabolic factors pointed towards an increased biological effect of OPG. Interestingly, OPG appears to be involved in OA progression by increasing two catabolic factors involved in cartilage pathophysiology.

Topics: Adult; Aged; Cells, Cultured; Chondrocytes; Dinoprostone; Humans; Interleukin-1beta; Middle Aged; Osteoarthritis, Knee; Osteoprotegerin; Polymerase Chain Reaction; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Tumor Necrosis Factor-alpha; Up-Regulation

To characterize bone microarchitectural changes and to test the hypothesis that disrupting local cytokine equilibrium could modify cartilage degradation in a murine model of experimental osteoarthritis (OA).. Ten-week-old male C57BL/6 mice underwent medial meniscectomy of their right knees and a sham operation of their left knees. The mice received intraperitoneal injections of osteoprotegerin (OPG) (10 mg/kg), interleukin-1 receptor antagonist (IL-1Ra) (100 mg/kg), or phosphate buffered saline for 6 weeks. The microarchitecture of the trabecular bone, the OA score, and expression of ADAMTS-4 and ADAMTS-5 were assessed. Proteoglycan release was measured in cartilage explant cultures in the presence of IL-1Ra and OPG.. In the meniscectomized knees, bone volume/tissue volume (BV/TV) was lower, whereas trabecular separation, the OA score, and aggrecanase expression were higher than in the sham-operated knees. After treatment with OPG, BV/TV was significantly increased and trabecular separation was reduced in the knees that underwent meniscectomy. The OA score and the number of ADAMTS-positive cells were significantly decreased by treatment with OPG but were not affected by IL-1Ra. Moreover, OPG did not directly reduce the release of proteoglycans from cartilage explant cultures.. In an experimental model of OA, meniscectomy induced bone loss and cartilage degradation at 6 weeks. Systemic administration of OPG prevented bone and cartilage degradation in vivo but had no effect on cartilage in vitro. These data collectively indicate that bone could be a contributor in the early stages of OA pathogenesis. They further suggest that disruption of RANKL/OPG balance might result in the degradation of cartilage subjected to mechanical loading. Specific targeting of the bone cytokine network might help to prevent OA.

Topics: ADAM Proteins; ADAMTS4 Protein; ADAMTS5 Protein; Animals; Bone and Bones; Cartilage Diseases; Cartilage, Articular; Disease Models, Animal; Interleukin 1 Receptor Antagonist Protein; Male; Menisci, Tibial; Mice; Mice, Inbred C57BL; Osteoarthritis, Knee; Osteoprotegerin; Procollagen N-Endopeptidase; Proteoglycans; RANK Ligand

Evaluation of serum and synovial fluid OPG and sRANKL in 37 patients with primary knee osteoarthritis.. OPG and sRANKL were measured using ELISA.. OPG, sRANKL and sRANKL/OPG were increased in osteoarthritis patients' serum. Synovial OPG was higher than serum OPG, while sRANKL/OPG was higher in the serum; both correlated with disease severity.. RANKL/OPG pathway is implicated in the pathogenesis of knee osteoarthritis being a suitable target for therapeutic intervention.

Topics: Aged; Aged, 80 and over; Biomarkers; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Osteoprotegerin; Radiography; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Severity of Illness Index; Synovial Fluid

To investigate the effect of osteoclastogenesis inhibitory factor/osteoprotegerin (OPG) on chondrocytes in the development of osteoarthritis (OA) in vivo.. To determine the role of endogenous OPG in the progression of OA, OA was surgically induced in OPG+/- mice and their wild-type (WT) littermates. To determine the role of exogenous OPG, knee joints of C57BL/6J mice with surgically induced OA were injected intraarticularly with recombinant human OPG (rHuOPG) or vehicle 5 times a week. All mice were euthanized 4 weeks after OA induction; joints were harvested and evaluated immunohistochemically.. Although OA changes were induced in both WT and OPG+/- mice, the degenerative changes in the articular cartilage were significantly enhanced in OPG+/- mice. In C57BL/6J mice with surgically induced OA, intraarticular OPG administration protected the articular cartilage from the progression of OA. The Mankin and cartilage destruction scores in OPG-treated animals were approximately 50% of those seen in the control group. Furthermore, OPG administration significantly protected articular cartilage thickness. Findings of the TUNEL assay indicated that rHuOPG prevented chondrocyte apoptosis in joints with surgically induced OA. Results of immunostaining indicated that OPG protein was detected in the synovium and in resident chondrocytes at higher levels in the OPG-treated group than in the control group.. These data indicate that endogenous OPG had a protective effect against the cartilage destruction that occurs during OA progression. Furthermore, direct administration of rHuOPG to articular chondrocytes prevented cartilage destruction in an experimental murine model of OA via prevention of chondrocyte apoptosis.

Topics: Adjuvants, Immunologic; Animals; Apoptosis; Cartilage, Articular; Chondrocytes; Disease Models, Animal; Immunohistochemistry; Injections, Intra-Articular; Mice; Mice, Inbred C57BL; Osteoarthritis, Knee; Osteoprotegerin

Topics: Arthritis, Rheumatoid; Carrier Proteins; Cells, Cultured; Fibroblasts; Glycoproteins; Humans; Knee Joint; Membrane Glycoproteins; Osteoarthritis, Knee; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synovial Membrane

To clarify the regulation of osteoprotegerin (OPG) expression in rheumatoid synovial fibroblasts by investigating the effect of tumor necrosis factor-alpha (TNF-alpha) and the mechanism of TNF-alpha-induced OPG expression.. OPG expression was examined by Northern blot hybridization and reverse transcriptase-polymerase chain reaction in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and subjects with no inflammatory condition. Amounts of OPG in conditioned medium were determined by ELISA. The effect of OPG on TNF-alpha-induced osteoclastogenesis was investigated in primary cultures of RA synovial cells.. OPG was highly expressed in RA synovial fibroblasts compared to OA and noninflammatory synovial fibroblasts. Different levels of OPG expression were found among patients with RA. TNF-alpha induced OPG expression in all synovial fibroblasts, even OA and noninflammatory fibroblasts, and expression occurred to a remarkable degree in RA fibroblasts. The OPG expression was upregulated by TNF-alpha in a time- and dose-dependent manner. TNF-alpha-induced OPG expression was inhibited by hymenialdisine, a nuclear factor-kappaB inhibitor, in a dose-dependent manner, and expression was inhibited by soluble TNF receptor/Fc fusion protein I (TNFs-RI/Fc), not by TNFs-RII/Fc. In contrast, TNF-alpha-induced osteoclastogenesis in primary cultures of RA synovial cells was inhibited by the addition of OPG.. These results suggest that OPG is highly expressed and is upregulated by TNF-alpha in rheumatoid synovial fibroblasts. TNF-alpha-induced OPG expression is mediated predominantly through TNF-RI. Although TNF-alpha is known to stimulate bone destruction, TNF-alpha-induced upregulation of OPG may contribute to self-protection from the bone destruction in RA.

Topics: Adult; Aged; Antigens, CD; Arthritis, Rheumatoid; Calcitriol; Carrier Proteins; Cells, Cultured; Female; Fibroblasts; Glycoproteins; Humans; Membrane Glycoproteins; Middle Aged; Osteoarthritis, Knee; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Synovial Membrane; Tumor Necrosis Factor-alpha

To demonstrate the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in synovial tissue from rheumatoid arthritis (RA) patients, establish the cell lineage expressing OPG and compare the expression of OPG in RA, spondyloarthropathies, osteoarthritis and normal synovial tissue.. Synovial biopsy specimens were obtained at arthroscopy from 16 RA and 12 spondyloarthropathy patients with active synovitis of a knee joint, six RA patients with no evidence of active synovitis, 10 patients with osteoarthritis and 18 normal subjects. Immunohistological analysis was performed using monoclonal antibodies (mAb) to detect OPG and RANKL expression. In addition, dual immunohistochemical evaluation was performed with lineage-specific monoclonal antibodies (macrophages, fibroblasts and endothelial cells) and OPG to determine the cell lineages expressing OPG. The sections were evaluated by computer-assisted image analysis and semiquantitative analysis.. Two patterns of OPG expression were seen, one exclusively in endothelial cells and one expressed predominantly in macrophages in the synovial lining layer. Both patterns of OPG staining could be blocked with excess recombinant OPG. Endothelial and synovial lining expression of OPG was seen in all synovial tissues except those from patients with active RA. In contrast, RANKL expression was seen predominantly in synovial tissue from patients with active disease, mainly in sublining regions, particularly within areas of lymphocyte infiltration.. OPG expression on macrophage type synovial lining cells as well as endothelial cells is deficient in RA patients with active synovitis, in contrast to that seen in spondyloarthropathy patients with active synovitis. This deficiency in OPG expression in the inflamed joint of RA patients may be important in the development of radiologically defined joint erosions.

Topics: Acute Disease; Adult; Aged; Arthritis; Arthritis, Rheumatoid; Arthroscopy; Blotting, Western; Carrier Proteins; Case-Control Studies; Endothelium; Female; Glycoproteins; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Knee Joint; Macrophages; Male; Membrane Glycoproteins; Middle Aged; Osteoarthritis, Knee; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Spondylarthropathies; Statistics, Nonparametric; Synovial Membrane

We studied the relationship between osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) concentration in synovial fluid from individuals with osteoarthritis (OA) of the knee and the severity of this condition. The study population included 111 Japanese women with knee OA (153 knees) and 23 normal controls. Osteoarthritic changes were graded according to the system of Kellgren and Lawrence. The concentration of OPG/OCIF in synovial fluid increased with severity of knee OA and was significantly higher in individuals with OA of grade IV than in those with OA of grade 0 or grade 1. It has been shown in a previous study that administration of OPG/OCIF prevents cartilage destruction in adjuvant-induced arthritis in rats. The increase in the concentration OPG/OCIF in synovial fluid of individuals with knee OA might thus reflect a compensatory response to degeneration of articular cartilage and serve to protect cartilage rather than be a cause of OA.

Topics: Aged; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Middle Aged; Osteoarthritis, Knee; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Synovial Fluid