Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Complement Component C5 Plays a Central Role in Osteoarthritis.
Robinson3, William, Rozelle1, Andrew L., Lindstrom, Tamsin M., Gobezie, Reuben, Holers4, V. Michael, Lee2, David M., Wang, Qian
Osteoarthritis (OA) is characterized by the breakdown of articular cartilage and is generally believed to result from "wear and tear". Although low-grade inflammatory responses are observed in OA, their contribution to its pathogenesis is unclear. We investigated a role for the complement systemand specifically complement component C5 and the membrane attack complex (MAC)in the pathogenesis of OA.
Proteins present in synovial fluids derived from OA patients were surveyed by mass spectrometry. ELISA analysis was used to assess activation of the complement cascade in OA synovial fluid and in serum incubated with cartilage proteins. Immunohistochemical staining with antibodies specific for the MAC (comprising complement components C5b-9) was performed on remnant cartilage tissue from patients with OA. Bioinformatic analysis was performed on RNA profile datasets from OA and healthy synovial membrane to determine relative levels of expression of the complement effectors and inhibitors identified by mass spectrometry. A murine model of OA, generated by surgical medial meniscectomy, was used to determine the susceptibility of mice deficient in complement component C5 to OA. Arthritis severity was assessed by histological analysis of toluidine-blue-stained joint sections and by gait analysis performed using the CatWalk System. Finally, qPCR and immunoassays were used to determine the effects of sublytic MAC on chondrocyte gene and protein expression.
Mass spectrometry analysis revealed the presence of multiple complement effectors and inhibitors in the synovial fluid of OA patients. ELISA analysis demonstrated elevations of C3a and C5b-9 in OA synovial fluids, indicating activation of the complement cascade. Further, synovium derived from OA patients was found to express complement components, whereas synovium from healthy individuals expressed complement inhibitors, suggesting that the synovium contributes to a local imbalance in the complement system in OA joints. Using an in vivo model of OA, we found that mice deficient in the central complement component C5 are protected against the development of degenerative arthritis, as assessed histologically and by gait analysis. Wild-type mice treated with an anti-C5 antibody were similarly protected. Moreover, the MAC (the cell-bound form of C5b-9) was detected on chondrocytes in cartilage from OA patients, and deposition of sublytic MAC on chondrocytes derived from OA cartilage induced the production of matrixdegrading enzymes, cell cycle regulators, inflammatory mediators, and complement components.
Our results suggest that local dysregulation of complement in synovial joints plays a critical role in the development of OA. Further, we demonstrate a critical role for the complement component C5 in the pathogenesis of experimental OA.
To cite this abstract, please use the following information:
Robinson, William, Rozelle, Andrew L., Lindstrom, Tamsin M., Gobezie, Reuben, Holers, V. Michael, Lee, David M., et al; Complement Component C5 Plays a Central Role in Osteoarthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2229