ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'.
ADAMTS and ADAM metalloproteinases in osteoarthritis - looking beyond the 'usual suspects'.
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DOI：
10.1016/j.joca.2017.02.791
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发表时间：
2017-07
影响因子：
7
通讯作者：
Troeberg L
中科院分区：
文献类型：
--
作者：
Yang CY;Chanalaris A;Troeberg L
基质金属蛋白酶（MMP）和“聚集蛋白聚糖酶”（具有血小板反应蛋白基序的解整合素和金属蛋白酶，ADAMTSs）通过降解细胞外基质（ECM）II型胶原和聚集蛋白聚糖在骨关节炎（OA）中发挥关键作用，因此是开发OA治疗的潜在靶点。本文旨在全面综述其他鲜为人知的ADAMTS和相关adamalysins（或解整合素和金属蛋白酶（亚当斯））在软骨中的表达和潜在作用，以期识别关节中潜在的保护性或稳态金属蛋白酶，并为随后的选择性抑制剂设计提供信息。使用PubMed术语“骨关节炎”和“ADAMTS”或“ADAM”进行全面文献检索。据报道，几种ADAMTS和亚当斯在OA中的表达增加。这些包括可能在软骨基质粘附中起作用的酶（例如，前胶原N-蛋白酶ADAMTS-2、ADAMTS-3和ADAMTS-14），软骨细胞分化和增殖（例如，ADAM 9、ADAM 10、ADAM 12），以及有助于软骨分解的酶（例如，胡萝卜素寡聚蛋白（COMP）降解ADAMTS-7和ADAMTS-12）。除了充分表征的MMP、ADAMTS-4和ADAMTS-5之外，许多其他ADAMTS和亚当斯在软骨中表达，并且一些在OA中显示显著改变的表达。旨在阐明这些酶在软骨中的病理生理作用的研究将有助于我们理解OA发病机制，并能够设计有效靶向金属蛋白酶介导的软骨降解的靶向抑制剂，同时保留软骨修复途径。
Matrix metalloproteinases (MMPs) and ‘aggrecanase’ a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are well established to play key roles in osteoarthritis (OA) through degradation of extracellular matrix (ECM) type II collagen and aggrecan, and are thus potential targets for development of OA therapies. This paper aims to provide a comprehensive review of the expression and potential roles of other, lesser-known ADAMTSs and related adamalysins (or a disintegrin and metalloproteinases (ADAMs)) in cartilage, with a view to identifying potentially protective or homeostatic metalloproteinases in the joint and informing consequent selective inhibitor design. A comprehensive literature search was performed using PubMed terms ‘osteoarthritis’ and ‘ADAMTS’ or ‘ADAM’. Several ADAMTSs and ADAMs were identified as having reportedly increased expression in OA. These include enzymes likely to play roles in cartilage matrix anabolism (e.g., the procollagen N-proteinases ADAMTS-2, ADAMTS-3 and ADAMTS-14), chondrocyte differentiation and proliferation (e.g., ADAM9, ADAM10, ADAM12), as well as enzymes contributing to cartilage catabolism (e.g., Cartilage oligomeric protein (COMP)-degrading ADAMTS-7 and ADAMTS-12). In addition to the well-characterised MMPs, ADAMTS-4 and ADAMTS-5, many other ADAMTSs and ADAMs are expressed in cartilage and several show significantly altered expression in OA. Studies aimed at elucidating the pathophysiological roles of these enzymes in cartilage will contribute to our understanding of OA pathogenesis and enable design of targeted inhibitors that effectively target metalloproteinase-mediated cartilage degradation while sparing cartilage repair pathways.