Studies on the destruction of articular cartilage by matrix metalloproteinases

基质金属蛋白酶（Matrix metalloproteinases, MMPs）由至少15种不同的分子组成，其活性受到其常见的金属蛋白酶组织抑制剂（timp -1,2,3,4）的严格调控。在目前的研究中，我们已经证明了膜型1基质金属蛋白酶（MT1-MMP）在人类骨关节炎软骨中高度表达，并与proMMP-2 （progelatinase a）的激活呈正相关。我们还发现MT1-MMP是一种细胞外基质（ECM）降解蛋白酶，能够消化间质胶原和聚集蛋白，同时也是proMMP-2的激活剂。在骨关节炎和类风湿关节炎中，软骨基质蛋白和SPARC过表达，提示这可能是软骨中表达的MMPs降解ECM成分的继发组织反应。实际上，刺激各种间充质细胞产生ECM的tgf - β是在MMPs降解tgf - β /decorin复合物后释放的。为了确定生产水平，还开发了MMP-7和MMP-8的三明治酶免疫测定法。关于TIMP-2抑制MT1-MMP的机制以及timp -1,2,3,4在骨关节炎和类风湿性关节炎软骨中的表达的研究项目正在进行中。

Matrix metalloproteinases (MMPs) are composed of at least 15 different molecules and their activities are strictly regulated by their common tissue inhibitors of metalloproteinases (TIMP-1,2,3,4). In the present studies, we have demonstrated that membrane-type 1 matrix metalloproteinase (MT1-MMP) is highly expressed in the human osteoarthritic cartilage showing a positive correlation with activation of proMMP-2 (progelatinase A). We have also revealed that MT1-MMP is an extracellular matrix (ECM) -degrading proteinase capable of digesting interstitial collagens and aggrecan as well as an activator of proMMP-2. In osteoarthritis and rheumatoid arthritis, cartilage matrix protein and SPARC were overexpressed, suggesting that it may be a tissue reaction secondary to the degradation of the ECM components by MMPs expressed in the cartilages. Actually, TGF-beta which stimulates ECM production in various mesenchymal cells was released after degradation of the TGF-beta/decorin complex by MMPs. To determine the production levels, sandwich enzyme immunoassays for MMP-7 and MMP-8 were also developed. Research projects on the mechanisms of MT1-MMP inhibition by TIMP-2 and expression of TIMP-1,2,3,4 in osteoarthritic and rheumatoid arthritic cartilages are now under way.