ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein
ADAMTS-12 associates with and degrades cartilage oligomeric matrix protein
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DOI：
10.1074/jbc.m513433200
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发表时间：
2006-06-09
影响因子：
4.8
通讯作者：
Di Cesare, Paul E.
中科院分区：
文献类型：
--
作者：
Liu, Chuan-ju;Kong, Wei;Di Cesare, Paul E.
由于细胞外基质分解导致的关节软骨损失是关节炎的标志。软骨寡聚基质蛋白（COMP）是关节软骨中一种重要的非胶原基质成分，其降解片段已在关节炎患者的软骨、滑液和血清中观察到。然而，COMP降解的分子机制和负责它的酶在很大程度上仍然未知。ADAMTS-12（一种具有血小板反应蛋白基序的去整合素和金属蛋白酶）在体外和体内均与COMP相关。ADAMTS-12仅选择性结合测试的四个功能结构域中的COMP的表皮生长因子样重复结构域。ADAMTS-12的四个C-末端TSP-1样重复序列被证明是其与COMP相互作用所必需和充分的。重组ADAMTS-12能够在体外消化COMP。ADAMTS-12的COMP降解活性需要Zn 2+的存在和适当的pH（7.5 - 9.5），并且患有骨关节炎和类风湿性关节炎的患者的软骨和滑膜中的ADAMTS-12水平显著高于正常软骨和滑膜。总之，这些研究结果表明，ADAMTS-12是一种新的COMP相互作用和降解酶，因此可能在COMP降解关节炎的发生和发展中发挥重要作用。
Loss of articular cartilage because of extracellular matrix breakdown is the hallmark of arthritis. Degradative fragments of cartilage oligomeric matrix protein (COMP), a prominent noncollagenous matrix component in articular cartilage, have been observed in the cartilage, synovial fluid, and serum of arthritis patients. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. ADAMTS-12 (a disintegrin and metalloprotease with thrombospondin motifs) was shown to associate with COMP both in vitro and in vivo. ADAMTS-12 selectively binds to only the epidermal growth factor-like repeat domain of COMP of the four functional domains tested. The four C-terminal TSP-1-like repeats of ADAMTS-12 are shown to be necessary and sufficient for its interaction with COMP. Recombinant ADAMTS-12 is capable of digesting COMP in vitro. The COMP-degrading activity of ADAMTS-12 requires the presence of Zn2+ and appropriate pH (7.5 - 9.5), and the level of ADAMTS-12 in the cartilage and synovium of patients with both osteoarthritis and rheumatoid arthritis is significantly higher than in normal cartilage and synovium. Together, these findings indicate that ADAMTS-12 is a new COMP-interacting and -degrading enzyme and thus may play an important role in the COMP degradation in the initiation and progression of arthritis.