Metalloproteinases were first identified as collagen cleaving enzymes and are now appreciated to play important roles in a wide variety of biological processes. The aberrant activity and dysregulation of the metalloproteinase family are linked to numerous diseases including cardiovascular and pulmonary diseases, chronic wounds, cancer, fibrosis and arthritis. Osteoarthritis (OA) is the most prevalent age-related joint disorder that causes pain and disability, but there are no disease-modifying drugs available. The hallmark of OA is loss of articular cartilage and elevated activities of matrix-degrading metalloproteinases are responsible. These enzymes do not exist in isolation and their activity is tightly regulated by a number of processes, such as transcription, proteolytic activation, interaction with their inhibitors, cell surface and extracellular matrix molecules, and endocytic clearance from the extracellular milieu. Here, we describe the functions and roles of metalloproteinase family in OA pathogenesis. We highlight recent studies that have illustrated novel mechanisms regulating their extracellular activity and impairment of such regulations that lead to the development of OA. We also discuss how to stop or slow down the degenerative processes by targeting aberrant metalloproteinase activity, which may in future become therapeutic interventions for the disease.

金属蛋白酶最初被鉴定为胶原蛋白裂解酶，现在被认为在多种生物过程中发挥着重要作用。金属蛋白酶家族的异常活性和失调与多种疾病有关，包括心血管和肺部疾病、慢性伤口、癌症、纤维化和关节炎。骨关节炎 (OA) 是最常见的与年龄相关的关节疾病，会导致疼痛和残疾，但目前尚无缓解疾病的药物。OA 的特点是关节软骨丧失，基质降解金属蛋白酶活性升高是造成这一现象的原因。这些酶并不是孤立存在的，它们的活性受到许多过程的严格调节，例如转录、蛋白水解激活、与其抑制剂、细胞表面和细胞外基质分子的相互作用以及细胞外环境的内吞清除。在这里，我们描述了金属蛋白酶家族在 OA 发病机制中的功能和作用。我们重点介绍最近的研究，这些研究阐明了调节其细胞外活动的新机制以及导致 OA 发展的此类调节的损害。我们还讨论了如何通过针对异常的金属蛋白酶活性来阻止或减缓退行性过程，这可能在未来成为该疾病的治疗干预措施。