Lee H, Sodek K L, Hwang Q, Brown T J, Ringuette M, Sodek J
CIHR Group in Matrix Dynamics, Faculty of Dentistry, Room 234, Fitzgerald Building, University of Toronto, 150 College Street, Toronto, ON, Canada M5S 3E2.
Biochem Soc Trans. 2007 Aug;35(Pt 4):704-6. doi: 10.1042/BST0350704.
Degradation of collagen is required for the physiological remodelling of connective tissues during growth and development, as well as in wound healing, inflammatory diseases, and cancer cell invasion. In remodelling adult tissues, degradation of collagen occurs primarily through a phagocytic pathway. While various steps in this pathway have been characterized, the enzyme required to fragment collagen fibrils for phagocytosis has not been identified. Laser confocal microscopy, transmission electron microscopy and biochemical assays were used to show that degradation of collagen substrates by fibroblasts correlated with the expression of the membrane-bound metalloproteinase MT1-MMP (membrane-type 1 matrix metalloproteinase). The MT1-MMP was localized to sites of collagen cleavage on the cell surface and also within the cells. In contrast with MT1-MMP, the gelatinase MMP-2 was not required for collagen phagocytosis. Similar analyses of several ovarian cancer, breast cancer and fibrosarcoma cells indicated that highly metastatic cells also degrade collagen through a phagocytic pathway that is mediated by MT1-MMP. Collectively, these studies demonstrate a pivotal role for catalytically active MT1-MMP in preparing collagen fibrils for phagocytic degradation by normal and transformed cells.
在生长发育、伤口愈合、炎症性疾病以及癌细胞侵袭过程中，结缔组织的生理性重塑需要胶原蛋白的降解。在成年组织重塑过程中，胶原蛋白的降解主要通过吞噬途径发生。虽然该途径中的各个步骤已得到表征，但尚未确定用于使胶原纤维断裂以进行吞噬作用所需的酶。利用激光共聚焦显微镜、透射电子显微镜和生化分析表明，成纤维细胞对胶原蛋白底物的降解与膜结合金属蛋白酶MT1-MMP（膜型1基质金属蛋白酶）的表达相关。MT1-MMP定位于细胞表面以及细胞内的胶原蛋白裂解部位。与MT1-MMP不同，明胶酶MMP-2不是胶原蛋白吞噬所必需的。对几种卵巢癌、乳腺癌和纤维肉瘤细胞的类似分析表明，高转移细胞也通过由MT1-MMP介导的吞噬途径降解胶原蛋白。总体而言，这些研究证明了具有催化活性的MT1-MMP在为正常细胞和转化细胞进行吞噬降解准备胶原纤维方面的关键作用。
