Role and Regulation of ADAMTS-12 in the Cartilage Catabolism

描述（由申请人提供）：骨关节炎（OA）是一种退行性关节疾病，主要发生在老年人中，其特征是关节软骨侵蚀和细胞外基质分解。软骨寡聚基质蛋白（COMP）是一种非胶原基质成分，在关节炎患者中观察到其显著的降解片段，作为软骨代谢的生物学标志物显示出很大的前景。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。我们实验室最近的工作使用功能性遗传筛选鉴定了锌金属蛋白酶ADAMTS- 7（ADAMTS：具有血小板反应蛋白基序的去整合素和金属蛋白酶）作为第一个COMP结合酶。随后的序列和结构分析显示，ADAMTS-12具有与ADAMTS-7相似的结构域组织，并且这两种酶形成ADAMTS家族中具有独特性质的亚组。这些发现，沿着事实，即ADAMTS-12，而不是ADAMTS-7，在OA软骨中显著上调，为我们的假设提供了基础，即ADAMTS-12是负责OA中COMP降解的主要生理酶。拟定研究的具体目的是（1）表征ADAMTS-12对COMP的降解并鉴定其裂解位点;（2）鉴定和表征ADAMTS-12的天然抑制剂。拟议的研究将为理解软骨catastrophic的分子机制提供新的信息，因此，通过直接应用ADAMTS-12或其类似物的抑制剂，有助于开发用于OA管理的新治疗方案。

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a degenerative joint disease that occurs primarily in older persons and is characterized by erosion of the articular cartilage and breakdown of extracellular matrix. Cartilage oligomeric matrix protein (COMP), a noncollagenous matrix component whose prominent degradative fragments have been observed in arthritic patients, shows great promise as a biological marker of cartilage metabolism. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. Recent work in our laboratory using a functional genetic screen identified the zinc-metalloproteinase ADAMTS- 7 (ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs) as the first COMP-binding enzyme. Subsequent sequence and structure analyses revealed that ADAMTS-12 has a domain organization similar to that of ADAMTS-7 and that the two enzymes form a subgroup with unique properties within the ADAMTS family. These findings, along with the fact that ADAMTS-12, and not ADAMTS-7, is significantly upregulated in the OA cartilage, provide a foundation for our hypothesis that ADAMTS-12 is the major physiological enzyme responsible for COMP degradation in OA. The specific aims of the proposed study are (1) to characterize the degradation of COMP by ADAMTS-12 and to identify its cleavage sites; and (2) to identify and characterize the naturally occurring inhibitors of ADAMTS-12. The proposed research will provide new information towards understanding the molecular mechanism of cartilage catabolism, and thusly, aid in the development of novel treatment regimes for the management of OA by directly applying inhibitors of ADAMTS-12 or its analogs.