Department of Medicine, Section of Rheumatology, Rush University Medical Center, 1611 W. Harrison St., Suite 510, Chicago, IL 60612, USA.
Curr Rheumatol Rep. 2013 Aug;15(8):350. doi: 10.1007/s11926-013-0350-2.
More than two decades of research has revealed a combination of proteases that determine cartilage degradation in osteoarthritis. These include metalloproteinases, which degrade the major macromolecules in cartilage, aggrecan and type II collagen, serine proteases, and cysteine proteases, for example cathepsin K. This review summarizes the function of proteases in osteoarthritis progression, as revealed by studies of genetically engineered mouse models. A brief overview of the biochemical characteristics and features of several important proteases is provided, with the objective of increasing understanding of their function. Published data reveal at least three enzymes to be major targets for osteoarthritis drug development: ADAMTS-5, MMP-13, and cathepsin K. In surgical models of osteoarthritis, mice lacking these enzymes are protected from cartilage damage and, to varying degrees, from bone changes. In-vivo studies targeting these proteases with selective small-molecule inhibitors have been performed for a variety of animal models. Mouse models will provide opportunities for future tests of the therapeutic effect of protease inhibitors, both on progression of structural damage to the joint and on associated pain.
二十多年的研究揭示了一系列蛋白酶，它们决定了骨关节炎中的软骨降解。这些蛋白酶包括金属蛋白酶，它们降解软骨中的主要大分子，如聚集蛋白聚糖和 II 型胶原，丝氨酸蛋白酶和半胱氨酸蛋白酶，例如组织蛋白酶 K。这篇综述总结了通过基因工程小鼠模型研究揭示的蛋白酶在骨关节炎进展中的作用。简要概述了几种重要蛋白酶的生化特征和特点，旨在提高对其功能的理解。已发表的数据表明，至少有三种酶是骨关节炎药物开发的主要靶点：ADAMTS-5、MMP-13 和组织蛋白酶 K。在骨关节炎的手术模型中，缺乏这些酶的小鼠可免受软骨损伤，并且在不同程度上免受骨改变的影响。针对这些蛋白酶的体内研究已经在各种动物模型中使用选择性小分子抑制剂进行了。针对这些蛋白酶的小鼠模型将为蛋白酶抑制剂的治疗效果提供未来的测试机会，包括对关节结构损伤的进展以及相关疼痛的治疗效果。
