Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis

Abstract

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 diseases, such as rheumatoid arthritis (RA) and osteoarthritis (OA). In this study we investigated the ability of COMP to regulate complement. Such capacity was previously shown for some cartilage proteins. Methods Regulation of complement by COMP was studied using functional assays in vitro. Interactions between complement proteins and COMP were investigated using direct binding assays and electron microscopy. Circulating COMP and COMP-C3b complexes in serum and synovial fluid from RA and OA patients and healthy controls were measured using a novel ELISA. Results We show in vivo evidence of complement activation by released COMP in the general circulation of patients with RA, but not OA patients. We found that COMP induces activation and deposition of C3b and C9 specifically via the alternative pathway of complement, which is attributable to a direct interaction between COMP and properdin. Furthermore, COMP inhibits 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 is demonstrated in inflammation in vivo where 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.

Moraxella catarrhalis Evades Host Innate Immunity via Targeting Cartilage Oligomeric Matrix Protein

“…Elevated levels of COMP in serum or synovial fluid correlate with autoimmune or joint inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, and systemic sclerosis (26)(27)(28). We showed that COMP also functions as a regulator of complement activity (22). COMP binds C1q and mannose-binding lectin to block the classical and lectin complement pathways, respectively.…”

“…The pentameric COMP is assembled through interchain disulfide bonds, and each monomer consists of an N-terminal cysteine-rich domain used for oligomerization. It contains four epidermal growth factor (EGF) domains, eight thrombospondin type 3 repeats, and a C-terminal globular domain (22). The primary function of COMP is to catalyze collagen fibrillogenesis and to stabilize ECM (23,24).…”

“…COMP binds C1q and mannose-binding lectin to block the classical and lectin complement pathways, respectively. COMP also directly interacts with properdin to activate the alternative pathway of complement, leading to deposition of C3b and C9 (22).…”

The C-type lectin of the aggrecan G3 domain activates complement

“…This has been proposed to contribute to the local pro-inflammatory milieu in joints of patients suffering from RA. C1q, the initiator of the classical pathway, binds to decorin [5,6], biglycan [5], fibronectin [7], laminin [8], osteoadherin [6], fibromodulin [9], cartilage oligomeric matrix protein (COMP) [10] and more weakly to lumican [6] and chondroadherin [6]. These interactions can result in inhibition of C1q (decorin, biglycan, COMP) or in activation of the classical pathway (fibromodulin, osteoadherin).…”

“…Interestingly, those extracellular matrix (ECM) molecules that activate C1q and the ensuing complement cascade also bind complement inhibitors such as factor H (FH) [6] and C4b-binding protein (C4BP) [11] in order to limit inflammation. Furthermore, COMP, an established marker of joint destruction, activates the alternative complement pathway [10,12].…”