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Dose-Dependent Effects of Gonadotropin Releasing Hormone on Matrix Metalloproteinase (MMP)-2, and MMP-9 and Tissue Specific Inhibitor of Metalloproteinases-1 Messenger Ribonucleic Acid Levels in Human Decidual Stromal Cells in Vitro

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

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 V6H 3V5, Canada. E-mail: peleung{at}interchange.ubc.ca.

Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue-specific inhibitor of matrix metalloproteinases (TIMPs), play key roles in the cyclic remodeling events that occur in the human endometrium in preparation for pregnancy. To date, the factors capable of regulating the expression of MMPs and TIMPs in the human decidua remain poorly characterized. The spatiotemporal expression of GnRH in the human endometrium during the menstrual cycle and early pregnancy suggests that this hormone may have a regulatory role in the development of this dynamic tissue. In view of these observations, we have examined the ability of GnRH to regulate MMP-2, MMP-9, and TIMP-1 mRNA levels in primary cultures of human decidual stromal cells using a quantitative competitive PCR strategy. GnRH was capable of increasing MMP-2 and MMP-9 mRNA levels in these primary cell cultures in a dose-dependent manner. The GnRH antagonist, antide, was capable of inhibiting the GnRH-mediated increase in the levels of the MMP-2 and MMP-9 mRNA transcripts present in these decidual stromal cells in a dose-dependent manner. In contrast, GnRH or antide did not have a significant effect on TIMP-1 mRNA level in these primary cell cultures at any of the concentrations used in these studies. Taken together, these observations suggest that GnRH plays an integral role in human implantation, by virtue of its ability to regulate the balance between MMP and TIMP expression in decidual cells.

These studies were supported by an operating grant from the Canadian Institutes of Health Research (CIHR) (to P.C.K.L. and C.D.M.). P.C.K.L. is the recipient of a career investigatorship from the Michael Smith Foundation for Health Research. C.D.M. is the recipient of a scholarship from the CIHR.

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

Abbreviations: ECM, Extracellular matrix; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GnRHR, GnRH receptor; MMP, matrix metalloproteinases; QC-PCR, quantitative competitive PCR; TIMP, tissue-specific inhibitor of matrix metalloproteinases; u-PA, urokinase plasminogen activator.

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