Roles of membrane-type matrix metalloproteinase in tissue organization.

基质金属蛋白酶（MMPs）是多细胞生物体中降解细胞外基质成分进行组织重塑的关键酶。由于MMPs是作为无活性的酶原（pro-MMPs）分泌的，因此它们必须在组织中被激活才能发挥作用。然而，很少有人知道在体内的生理激活剂，积极组织重塑正在发生。我们最近确定了一种膜型MMP（MT-MMP）作为MMP-2（明胶酶原A=72-kDa IV型胶原酶原）的激活剂，其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-MMP是否在小鼠胚胎发生过程中激活MMP-2前体中发挥作用。MT-MMP、MMP-2及其抑制剂TIMP-2在胚胎中的表达随孕龄的增加而增加，随出生后的成熟而下降，MT-MMP转录本及其产物定位于MMP-2和TIMP-2均阳性表达的子宫内膜组织细胞中。在从观察到三种基因表达的显微切割组织制备的裂解物中检测到活化的MMP-2。MMP-2的激活与MMP-2和MT-MMP的表达成正比，提示MMP-2及其激活剂MT-MMP是生物体广泛使用的启动细胞表面组织重塑的系统。

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.