AN AUTOCRINE PARACRINE ROLE OF HUMAN DECIDUAL RELAXIN .1. INTERSTITIAL COLLAGENASE (MATRIX METALLOPROTEINASE-1) AND TISSUE-PLASMINOGEN ACTIVATOR/

Decidual and placental relaxins have been proposed as autocrine/paracr ine hormones in the remodeling of collagen in the amnion and chorion i n the last weeks of pregnancy. The matrix metalloproteinase-l (MMP-1) is a key enzyme in the degradation of the interstitial collagens which predominate in the fetal membranes. Distribution of the MMP-1 gene an d of the MMP-1 protein was shown by in situ hybridization and immunolo calization, respectively, in amnion, chorion, and decidua collected fr om patients before the onset of spontaneous labor. The distribution of MMP-1 in the chorionic cytotrophoblast and decidua coincided with tha t of the human relaxin receptor, detected by tissue section autoradiog raphy in tissues collected at the same stage of pregnancy. Fetal membr ane explants were used to study the effect of exogenous human relaxin HZ, These responded by a dose-dependent increase in expression of the MMP-1 gene, in its secreted protein, and in its enzyme activity in the medium. A similar dose-dependent increase in the tissue plasminogen a ctivator (tPA) gene and protein upon exposure of the explants to relax in H2 suggested a coordinated cascade system, resulting in increases i n secreted activities of MMP-1, MMP-3 (stromelysin), and MMP-9 (gelati nase B). There was no effect on the genes or proteins for MMP-2 (gelat inase A) or tissue inhibitor of metalloproteinase-l (TIMP-1), showing the specificity of the response. This coordinated regulation by relaxi n H2 of tPA,MMP-1, MMP-3, and MMP-9 would result in more complete degr adation of the fetal membrane extracellular matrix components.