15,16 Moreover, aberrant MMP expression has been implicated in pregnancy abnormalities, including IUGR and preeclampsia.17,18 http://www.selleckchem.com/products/PF-2341066.html MMP activity in any given tissue is a function of MMP gene expression, mRNA translation, and the action of various regulators of MMP action. MMP regulators, such as TIMPs, exert their affect either directly by binding to MMPs or indirectly by activating nuclear transcription factors that control the expression of select MMP genes. Appropriate trophoblast invasion and vascularization requires a functional synergism between MMPs and their regulating factors. For example, trophoblast invasion can be increased by either upregulating MMP expression or downregulating TIMP expression.
19 MMPs are inhibited by TIMPs, which are composed of a family of four endogenously expressed extracellular proteins (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) that act as specific protease inhibitors.20 Typically, TIMPs inhibit MMPs once they are activated by binding to the highly conserved zinc-binding site of active MMPs. Among the TIMP family, TIMP-1 preferentially inhibits MMP-9.21 In some cases, however, MMPs form complexes with TIMPs while they are still in their latent form. For example, the complex of pro-MMP-2 and TIMP-2 serves to promote the activation of pro-MMP-2 at the cell surface by the membrane-bound MMP, MMP-14.22 A decrease in TIMP-2 expression leads to a reduction in MMP-2/TIMP-2/MMP-14 complex formation and an inhibition of trophoblast invasion.
13 By regulating pro-MMP activation, extracellular matrix turnover, cell proliferation, apoptosis, and angiogenesis through both MMP-dependent and MMP-independent pathways, TIMPs serve important roles in numerous physiological processes including embryo implantation, reproductive tissue remodeling, and wound healing.23 Differential expression of TIMPs has also been shown in various cancer cells,23 suggesting that these proteins may also be important in cancer invasion and metastasis. Reverse transcriptase polymerase chain reaction analysis has detected mRNA expression of all four TIMPs in first trimester cytotrophoblast cells as well as endometrial stromal cells, uterine NK cells, and myofibroblasts.14 Regulation of MMP and TIMP Expression Trophoblast invasion in the first trimester is regulated both temporally and spatially. This appears to be mediated both in an autocrine fashion by trophoblastic factors and in a paracrine fashion by uterine factors.
A number of factors have been shown to regulate the synthesis, activation, and/or secretion of MMPs and TIMPs at the maternal-fetal interface, including a variety of cytokines, chemokines, growth factors, GSK-3 hormones, and oxygen tension.24,25 Urokinase Plasminogen Activator System The urokinase plasminogen activator (uPA) system��which includes uPA, uPA receptor (uPAR), and two major uPA inhibitors (PAI-1 and PAI-2)��has a broad spectrum of substrates and is involved primarily in tissue remodeling.