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Regulatory Effects of Gonadotropin-Releasing Hormone (GnRH) I and GnRH II on the Levels of Matrix Metalloproteinase (MMP)-2, MMP-9, and Tissue Inhibitor of Metalloproteinases-1 in Primary Cultures of Human Extravillous Cytotrophoblasts

Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5

Address all correspondence and requests for reprints to: Peter C. K. Leung, Ph.D., Department of Obstetrics and Gynecology, University of British Columbia, Room 2H-30, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5. E-mail: peleung{at}interchange.ubc.ca.

An intricate balance between the production of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), modulates the overall proteolytic activity of trophoblasts during human implantation. In these studies we have examined the ability of classical GnRH I and the second form of this hormone (GnRH II) to regulate MMP-2, MMP-9, and TIMP-1 mRNA and protein levels in extravillous cytotrophoblasts propagated from explants of first trimester chorionic villi. GnRH I and GnRH II were found to increase MMP-2 and MMP-9 mRNA and protein levels in these primary cell cultures in a dose- and time-dependent manner using quantitative competitive-PCR and ELISA. In contrast, these two hormones decreased trophoblastic TIMP-1 mRNA and protein levels. Cetrorelix, a GnRH receptor antagonist, inhibited the regulatory effects of GnRH I, but not GnRH II, on MMP-2, MMP-9, and TIMP-1 expression in these cells. Collectively, these observations suggest that GnRH I and GnRH II differentially regulate MMP-2, MMP-9, and TIMP-1 expression in human trophoblasts, possibly via distinct receptor-mediated intracellular signaling pathways.

This work was supported by an operating grant from the Canadian Institutes of Health Research (to P.C.K.L. and C.D.M.).

C.D.M. and P.C.K.L. contributed equally to these studies.

C.D.M. is a career investigator with the British Columbia Research Institute for Children’s and Women’s Health.

P.C.K.L. is the recipient of a distinguished senior investigatorship scholar award from the Michael Smith Foundation for Health Research.

Abbreviations: EVT, Extravillous cytotrophoblast; FBS, fetal bovine serum; GnRHR, GnRH receptor; MMP, matrix metalloproteinase; QC-PCR, quantitative competitive-PCR; TIMP, tissue inhibitor of metalloproteinases; uPA, urokinase plasminogen activator.

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