Roles of membrane-type matrix metalloproteinase in tissue organization.

基质金属蛋白酶(MMPs)是降解细胞外基质成分，参与多细胞生物体组织重塑的关键酶。由于MMPs是以非活性酶原(Pro-MMPs)的形式分泌的，它们必须在组织中被激活才能发挥作用。然而，对体内发生活性组织重塑的生理激活剂知之甚少。我们最近发现了一种膜型基质金属蛋白酶(MT-MMP)，它是前-基质金属蛋白酶-2(前-明胶酶A=72-kDa IV型前胶原酶)的激活剂，在侵袭性肿瘤中表达，并负责基底膜中IV型胶原的降解。在这项研究中，我们研究了MT-基质金属蛋白酶在小鼠胚胎发育过程中是否在激活原基质金属蛋白酶-2中发挥作用。MT-基质金属蛋白酶及其抑制物TIMP-2在胚胎中的表达随着胎龄的增加而增加，出生后随着胎龄的增加而降低。MT-基质金属蛋白酶转录本及其产物定位于骨化组织的细胞中，同时检测到基质金属蛋白酶-2和基质金属蛋白酶抑制剂-2。从显微解剖组织制备的裂解液中检测到活化的基质金属蛋白酶-2，观察到这三种基因的表达。活化的MMP2与MMP2和MT-MMP的表达成正比，提示MMP2及其激活剂MT-MMPs是生物体启动细胞表面组织重塑的一个广泛使用的系统。

Matrix metalloproteinases (MMPs) are pivotal enzymes for tissue remodeling of multicellular organisms by degrading the components of extracellular matrix. Since MMPs are secreted as inactive zymogens (pro-MMPs), they have to be activated in the tissue to function. However little is known about physiological activators in vivo where active tissue remodeling is taking place. We recently identified a membrane-type MMP (MT-MMP) as an activator of pro-MMP-2 (pro-gelatinase A=72-kDa type IV pro-collagenase) that is expressed in invasive tumors and is responsible for degradation of type IV collagen in the basement membrane. In this study we examined whether MT-MMP plays a role in activating pro-MMP-2 during mouse embryogenesis. MT-MMP expression was increased together with that of MMP-2 and its inhibitor TIMP-2 in embryos according to the days after gestation and decreased with maturation after birth.MT-MMP transcripts and the product were localized in the cells of the occificating tissues where both MMP-2 and TIMP-2 were detected. Activated MMP-2 was detected in the lysate prepared from the microdissected tissue where expression of the three genes were observed. Activated MMP-2 was propotional to the expression of MMP-2 and MT-MMP.Thus the results indicate that MMP-2 and its activator MT-MMP is a widely used system for organisms to initiate tissue remodeling on the cell surface.