Corticotropin-Releasing Hormone and Urocortin Induce Secretion of Matrix Metalloproteinase-9 (MMP-9) without Change in Tissue Inhibitors of MMP-1 by Cultured Cells from Human Placenta and Fetal Membranes

Abstract

Matrix metalloproteinases (MMPs) are essential for human parturition due to their degrading of the extracellular matrix. CRH and urocortin (Ucn) are thought to play a central role in the mechanisms controlling human pregnancy and parturition. The aim of this study was to assess the effects of CRH and Ucn on MMP-9 and tissue inhibitors of MMP-1 (TIMP-1) protein and/or mRNA levels in vitro. Zymography, Western blotting, real-time RT-PCR, and culture/treatments of purified sycytiotrophoblast, chorion trophoblast, and amniotic epithelial cells from human placenta and fetal membranes were performed. CRH and Ucn significantly increased MMP-9 protein secretion from cultured chorionic trophoblast, amnion epithelial, and syncytiotrophoblast cells (P < 0.01, compared with control, respectively), but there was no effect on TIMP-1 secretion and MMP-9 mRNA expression. Antalarmin (a CRH receptor type 1 antagonist) significantly blocked CRH- and Ucn-induced pro-MMP-9 secretion from three cell types (P < 0.01, compared with treatment with CRH and Ucn alone, respectively). Antisauvagine 30 (a CRH receptor type 2 antagonist) resulted in a significant reduction in CRH- and Ucn-induced secretion from chorionic trophoblast cells (P < 0.05) and syncytiotrophoblast cells (P < 0.01) compared with treatment with CRH and Ucn alone, respectively, but had no significant effect on amniotic epithelial cells. Our results suggest that CRH and Ucn may play a role in the mechanisms controlling human parturition and preterm delivery not only by affecting myometrial contractility, but also by increasing local MMP activity in placenta and fetal membranes, thereby contributing to membrane rupture with the onset and progression of human labor.