Brief Report: Carboxypeptidase B Serves as a Protective Mediator in Osteoarthritis

Abstract

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). In this study, we investigated whether CPB has 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 four months later histologically assessing cartilage damage, osteophyte formation, and synovitis in the mouse stifle joints. 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 ELISA, 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 wild-type mice (P<0.01) and had a greater number of osteophytes (P<0.05) and degree of synovitis (P<0.05). In synovial fluids 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. Conclusions Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…In contrast, collagen IX, properdin, and CD59 can act as inhibitors of complement (107). In recent studies, mice with impaired ability to generate the complement membrane attack complex (MAC) were partially spared from the development of OA, showing direct evidence of role of complement system in OA pathogenesis (108). However, the way complement deposition occur in joint synovium of OA, and the role of the complement cascade in the pathogenesis remain to be precisely determined.…”

The Role of Innate Immunity in Osteoarthritis: When Our First Line of Defense Goes On the Offensive

“…Pharmacologically blocking the complement system by CR2-fH, a fusion protein of a complement receptor and the naturally occurring inhibitor factor H, was associated with less severe joint damage (35). The same group showed that carboxypeptidase B (CPB) appeared to have a protective role in OA by inhibiting the complement system (55). Similar to their previous findings (35), in a medial menisectomy OA model, mice that were deficient for CPB showed more cartilage degeneration, osteophyte formation and synovitis than wild-type mice (55).…”

“…The same group showed that carboxypeptidase B (CPB) appeared to have a protective role in OA by inhibiting the complement system (55). Similar to their previous findings (35), in a medial menisectomy OA model, mice that were deficient for CPB showed more cartilage degeneration, osteophyte formation and synovitis than wild-type mice (55). In addition, they found that levels of CPB correlated to levels of MAC in the synovial fluid of patients with OA; suggesting that CPB has an anti-inflammatory role in the joint (55).…”

A Systems View of Risk Factors for Knee Osteoarthritis Reveals Insights into the Pathogenesis of the Disease

“…Indeed, the vulnerability may arise when individuals with altered or compromised joint biology sustain injury or altered loading. 12, 33 Thus a simple “wear and tear” explanation does not provide a sufficient basis to move forward with new prevention modalities or new methods for early detection of OA as a better understanding of OA at a systems level is needed.…”