Analyzes on ECM metabolism in transgenic and knockout mice

在基质金属蛋白酶（MMP）基因家族成员中，MMP-2（明胶酶A）被认为参与癌症侵袭和转移以及关节破坏，因此其在体内的功能是重要的。膜型基质金属蛋白酶（Membrane-type MMPs，MT-MMPs）是近年来发现的一种MMP-2前体的活性物质，其对细胞外基质的降解机制是MMP研究领域的热点之一。在本研究中，我们已经证明，proMMP-2的激活是由MT 1-MMP介导的人浸润性乳腺癌和人甲状腺癌。在人骨关节炎和类风湿关节炎软骨中，MT 1-MMP也在proMMP-2的激活中起主要作用，显示与软骨破坏正相关。我们还发现，MT 1-MMP是一种细胞外基质降解蛋白酶，能够消化间质胶原和聚集蛋白聚糖以及proMMP-2的激活剂。MT3-MMP对除I型胶原外的其他底物的活性相似。正在制造在软骨中特异性表达MT 1-MMP的转基因小鼠，并且正在对其表型进行分析。这些小鼠将与日本研究小组制造的MMP-2敲除小鼠回交，并检查其表型。

Among the matrix metalloproteinase (MMP) gene family members, MMP-2 (gelatinase A) is believed to be involved in cancer invasion and metastasis and joint destruction, and thus its function in vivo is important. Membrane-type MMPs (MT-MMPs) were recently cloned as acribators of proMMP-2 and the degradation mechanism of extracellular matrix by the MT-MMPs/MMP-2 system is one of the key projects in the field of MMP research. In the present studies, we have demonstrated that proMMP-2 activation is mediated by MT1-MMP in the human invasive breast carcinomas and human thyroid carcinomas. In the human osteoarthritic and rheumatoid arhtritic cartilages, MT1-MMP also playd a major role in the activation of proMMP-2, showing a positive correlation with cartilage destruction. We also revealed that MT1-MMP is an extracellular matrix-degrading proteinase capable of digesting interstitial collagens and aggrecan as well as an activator of proMMP-2. MT3-MMP had a similar acitivity against these substrates except for type I collagen. Transgenic mice expressing MT1-MMP specifically in the cartilages are being made and analyzes of their phenotypes are now under way. These mice will be back crossed with MMP-2 knockout mice which had been made by a Japanese group and their phenotypes will be examined.