Nixon J S, Bottomley K M, Broadhurst M J, Brown P A, Johnson W H, Lawton G, Marley J, Sedgwick A D, Wilkinson S E
Research Centre, Roche Products Ltd., Welwyn Garden City, Herts., United Kingdom.
Int J Tissue React. 1991;13(5):237-41.
The matrix metalloproteinases (MMPs) collagenase, gelatinase and stromelysin, contribute to the destruction of articular cartilage which occurs during rheumatoid and osteoarthritis. Ro 31-4724, a substrate analogue containing a hydroxamic acid function, is a potent but non-selective inhibitor of all three MMPs (I50, collagenase = 10 nM), whereas Ro 31-7467, a phosphinic acid transition-state analogue, shows 14-fold and 12-fold selectivity for collagenase (I50 = 17 nM) over gelatinase and caseinase (stromelysin) respectively. The effects of these inhibitors on interleukin-1-induced bovine nasal cartilage degradation were examined. The hydroxamate Ro 31-4724 inhibits proteoglycan and collagen loss, whereas the phosphinic acid Ro 31-7467 selectively inhibits collagen breakdown in this model. This represents the first demonstration of potent and selective inhibition of IL1-induced cartilage degradation in vitro by MMP inhibitors. These results suggest that collagenase is responsible for collagen loss and that a different enzyme, possibly stromelysin, is responsible for proteoglycan degradation in this model.
基质金属蛋白酶（MMPs）中的胶原酶、明胶酶和基质溶素，会导致类风湿性关节炎和骨关节炎期间发生的关节软骨破坏。Ro 31 - 4724是一种含有异羟肟酸功能的底物类似物，是这三种MMPs的强效但非选择性抑制剂（I50，胶原酶 = 10 nM），而次膦酸过渡态类似物Ro 31 - 7467对胶原酶（I50 = 17 nM）分别显示出比对明胶酶和酪蛋白酶（基质溶素）高14倍和12倍的选择性。研究了这些抑制剂对白细胞介素 - 1诱导的牛鼻软骨降解的影响。异羟肟酸Ro 31 - 4724抑制蛋白聚糖和胶原蛋白的流失，而次膦酸Ro 31 - 7467在该模型中选择性抑制胶原蛋白的分解。这是首次证明MMP抑制剂在体外对IL1诱导的软骨降解具有强效和选择性抑制作用。这些结果表明，在该模型中，胶原酶是导致胶原蛋白流失的原因，而一种不同的酶，可能是基质溶素，是导致蛋白聚糖降解的原因。
