Studies on the destruction of articular cartilage by matrix metalloproteinases

基质金属蛋白酶(MMPs)由至少15个不同的分子组成，它们的活性受到它们共同的金属蛋白酶组织抑制物(TIMP-1，2，3，4)的严格调控。在本研究中，我们发现膜型基质金属蛋白酶1(MT1-MMPs)在人骨关节炎软骨中高表达，并与原MMP2(孕激素酶A)的激活呈正相关。我们还发现MT1-MMPs是一种降解细胞外基质(ECM)的蛋白水解酶，能够消化间质中的胶原蛋白和蛋白聚糖，同时也是原MMP2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成分所致的组织反应。事实上，促进多种间充质细胞产生ECM的转化生长因子-β是在基质金属蛋白酶降解转化生长因子-β/核心蛋白复合体后释放出来的。为了确定产生水平，还建立了检测基质金属蛋白酶-7和基质金属蛋白酶-8的夹心酶联免疫测定法。关于TIMP-2抑制MT1-MMPs的机制以及TIMP-1、2、3、4在骨关节炎和类风湿关节炎软骨中的表达的研究正在进行中。

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.