Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis.

OBJECTIVE: We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). We undertook this study to investigate whether CPB plays a role in the pathogenesis of OA. METHODS: We compared the development of OA in CPB-deficient (Cpb2(-/-) ) mice and wild-type mice by subjecting them to medial meniscectomy and histologically assessing cartilage damage, osteophyte formation, and synovitis in the stifle joints 4 months later. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used enzyme-linked immunosorbent assay, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)-a complement effector critical to OA pathogenesis. RESULTS: Cpb2(-/-) mice developed dramatically greater cartilage damage than did wild-type mice (P < 0.01) and had a greater number of osteophytes (P < 0.05) and a greater degree of synovitis (P < 0.05). In synovial fluid samples from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis. CONCLUSION: Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.

Increased serum concentrations of visfatin and its production by different joint tissues in patients with osteoarthritis.

BACKGROUND: The goal of this study was to investigate the distribution of visfatin in paired serum and synovial fluid (SF) samples from patients with osteoarthritis (OA), and in serum from healthy controls. In addition, we wished to determine the potential sources of visfatin in joint tissue. METHODS: Twenty-three patients with OA requiring total knee arthroplasty (TKA), 17 healthy subjects and ten donors requiring amputation were included in the study. Concentrations of visfatin in serum and SF were analyzed using an enzyme-linked immunosorbent assay (ELISA). The concentration of visfatin was also measured in conditioned media from cultured joint tissues. RESULTS: We found serum visfatin concentrations to be higher in patients with OA compared to healthy controls (p<0.05), and SF-visfatin concentrations exceeded those in paired serum (p=0.004). In addition, infrapatellar fat pad and synovium were important sources of visfatin, while osteophytes released largest amounts of visfatin. Therefore, osteophytes can be considered a major source of visfatin in the knee joint in patients with OA. CONCLUSIONS: These results suggest that visfatin may be involved in the pathophysiology of OA and may have local effects in the joint during the process of OA.

Transglutaminase-2 differently regulates cartilage destruction and osteophyte formation in a surgical model of osteoarthritis.

Osteoarthritis is a progressive joint disease characterized by cartilage degradation and bone remodeling. Transglutaminases catalyze a calcium-dependent transamidation reaction that produces covalent cross-linking of available substrate glutamine residues and modifies the extracellular matrix. Increased transglutaminases-mediated activity is reported in osteoarthritis, but the relative contribution of transglutaminases-2 (TG2) is uncertain. We describe TG2 expression in human femoral osteoarthritis and in wild-type and homozygous TG2 knockout mice after surgically-induced knee joint instability. Increased TG2 levels were observed in human and wild-type murine osteoarthritic cartilage compared to the respective controls. Histomorphometrical but not X-ray investigation documented in osteoarthritic TG2 knockout mice reduced cartilage destruction and an increased osteophyte formation compared to wild-type mice. These differences were associated with increased TGFbeta-1 expression. In addition to confirming its important role in osteoarthritis development, our results demonstrated that TG2 expression differently influences cartilage destruction and bone remodeling, suggesting new targeted TG2-related therapeutic strategies.