Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis.
Regulation of complement by cartilage oligomeric matrix protein allows for a novel molecular diagnostic principle in rheumatoid arthritis.
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DOI：
10.1002/art.27720
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发表时间：
2010-12
影响因子：
--
通讯作者：
Blom AM
中科院分区：
文献类型：
--
作者：
Happonen KE;Saxne T;Aspberg A;Mörgelin M;Heinegård D;Blom AM
软骨寡聚基质蛋白（COMP）是软骨的结构组分，在软骨中它催化胶原原纤维形成。在与活动性关节疾病如类风湿性关节炎（RA）和骨关节炎（OA）相关的软骨更新增加期间，在血清中发现COMP量升高。在这项研究中，我们研究了COMP调节补体的能力。这种能力先前在一些软骨蛋白中显示。使用体外功能测定研究COMP对补体的调节。补体蛋白和COMP之间的相互作用进行了研究，使用直接结合试验和电子显微镜。使用新的ELISA测量来自RA和OA患者和健康对照的血清和滑液中的循环COMP和COMP-C3 b复合物。我们在体内的证据表明，补体激活释放COMP类风湿关节炎患者的全身循环，但没有OA患者。我们发现COMP通过补体旁路途径特异性地诱导C3 b和C9的活化和沉积，这归因于COMP和备解素之间的直接相互作用。此外，COMP抑制经典和凝集素补体途径，由于直接相互作用的茎区的C1 q和甘露糖结合凝集素，分别。COMP是第一种在体内炎症中表现出活性作用的细胞外基质蛋白，其中它可以激活一种补体途径，同时具有抑制另一种补体途径的潜力。这些相互作用的净结果很可能由释放的COMP片段的类型决定，这可能是疾病特异性的。
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. 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. 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. 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.