Journal
ARTHRITIS AND RHEUMATISM
Volume 62, Issue 12, Pages 3574-3583Publisher
WILEY
DOI: 10.1002/art.27720
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Funding
- Swedish Research Council
- Swedish Foundation for Strategic Research
- NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
- European Community
- Knut and Alice Wallenberg Foundation
- Alfred Osterlund Foundation
- Greta and Johan Kock Foundation
- Inga-Britt and Arne Lundberg Foundation
- King Gustav Vth's 80th Anniversary Foundation
- University Hospital in Malmo/Lund
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Objective. Cartilage oligomeric matrix protein (COMP) is a structural component of cartilage, where it catalyzes collagen fibrillogenesis. Elevated amounts of COMP are found in serum during increased turnover of cartilage associated with active joint disease, such as rheumatoid arthritis (RA) and osteoarthritis (OA). This study was undertaken to investigate the ability of COMP to regulate complement, a capacity that has previously been shown for some other cartilage proteins. Methods. Regulation of complement by COMP was studied using functional in vitro assays. Interactions between complement proteins and COMP were investigated by direct binding assay and electron microscopy. Circulating COMP and COMP-C3b complexes in serum and synovial fluid from RA and OA patients and healthy controls were measured with a novel enzyme-linked immunosorbent assay. Results. We found in vivo evidence of complement activation by released COMP in the general circulation of patients with RA, but not patients with OA. COMP induced activation and deposition of C3b and C9 specifically via the alternative pathway of complement, which was attributable to direct interaction between COMP and properdin. Furthermore, COMP inhibited the classical and the lectin complement pathways due to direct interaction with the stalk region of C1q and mannose-binding lectin, respectively. Conclusion. COMP is the first extracellular matrix protein for which an active role in inflammation has been demonstrated in vivo. It can activate one complement pathway at the same time as it has the potential to inhibit another. The net outcome of these interactions is most likely determined by the type of released COMP fragments, which may be disease specific.
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