Department of Laboratory Medicine, Division of Medical Protein Chemistry, Lund University, Malmö, Sweden.
PLoS One. 2013 Apr 15;8(4):e61407. doi: 10.1371/journal.pone.0061407. Print 2013.
Excessive complement activation contributes to joint diseases such as rheumatoid arthritis and osteoarthritis during which cartilage proteins are fragmented and released into the synovial fluid. Some of these proteins and fragments activate complement, which may sustain inflammation. The G3 domain of large cartilage proteoglycan aggrecan interacts with other extracellular matrix proteins, fibulins and tenascins, via its C-type lectin domain (CLD) and has important functions in matrix organization. Fragments containing G3 domain are released during normal aggrecan turnover, but increasingly so in disease. We now show that the aggrecan CLD part of the G3 domain activates the classical and to a lesser extent the alternative pathway of complement, via binding of C1q and C3, respectively. The complement control protein (CCP) domain adjacent to the CLD showed no effect on complement initiation. The binding of C1q to G3 depended on ionic interactions and was decreased in D2267N mutant G3. However, the observed complement activation was attenuated due to binding of complement inhibitor factor H to CLD and CCP domains. This was most apparent at the level of deposition of terminal complement components. Taken together our observations indicate aggrecan CLD as one factor involved in the sustained inflammation of the joint.
补体过度激活可导致类风湿关节炎和骨关节炎等关节疾病，在此类疾病中，软骨蛋白发生断裂并释放到滑液中。这些蛋白和片段中的一些会激活补体，从而可能导致炎症持续存在。大型软骨蛋白聚糖聚集素的 G3 结构域通过其 C 型凝集素结构域（CLD）与其他细胞外基质蛋白（纤连蛋白和 tenascin）相互作用，并在基质组织中具有重要功能。在正常的聚集素转化过程中会释放含有 G3 结构域的片段，但在疾病中释放的片段越来越多。我们现在表明，聚集素 G3 结构域的 CLD 部分通过分别与 C1q 和 C3 的结合，激活经典补体途径和在较小程度上激活替代补体途径。紧邻 CLD 的补体控制蛋白（CCP）结构域对补体起始没有影响。C1q 与 G3 的结合取决于离子相互作用，在 D2267N 突变 G3 中减少。然而，由于补体抑制剂因子 H 与 CLD 和 CCP 结构域的结合，观察到的补体激活被减弱。这在末端补体成分沉积水平上最为明显。总之，我们的观察结果表明，聚集素 CLD 是参与关节持续炎症的一个因素。
