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Regulation of Matrix Metalloproteinase-9/Gelatinase B Expression and Activation by Ovarian Steroids and LEFTY-A/Endometrial Bleeding-Associated Factor in the Human Endometrium

Cell Biology Unit, Christian de Duve Institute of Cellular Pathology (P.B.C., C.G., Y.E., P.J.C., E.M., P.H.), and Department of Pathology, Saint-Luc University Clinics (C.G., E.M.), Université Catholique de Louvain, B-1200 Brussels, Belgium

Address all correspondence and requests for reprints to: Etienne Marbaix, Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Avenue Hippocrate, 75, B-1200 Brussels, Belgium. E-mail: marbaix{at}cell.ucl.ac.be.

Various matrix metalloproteinases (MMPs) participate in the menstrual breakdown of the human endometrium. MMP-9/gelatinase B is proposed as a major factor because it degrades many extracellular matrix constituents, including in the vasculature. Although globally under ovarian steroids control, endometrial MMP-9 seems expressed differently than other MMPs, and conflicting publications prevent a clear understanding of its regulation. We therefore quantified MMP-9 expression in the cycling human endometrium, defined its localization, and analyzed its regulation by estradiol and progesterone and by LEFTY-A/endometrial bleeding-associated factor in explant cultures. In fresh tissues, a major increase in MMP-9 mRNA expression occurred at menstruation, after a larger increase in LEFTY-A mRNA. MMP-9 was immunodetected in all cell types throughout the cycle, especially in foci of stromal cells during menstruation. MMP-9 synthesis by these cells was confirmed in cultured explants. In proliferative explants, ovarian steroids slightly decreased MMP-9 mRNA. They had no consistent effect on MMP-9 release in culture medium but strongly inhibited proMMP-9 activation. Addition of recombinant LEFTY-A to explants induced MMP-9 in most samples, a response prevented by ovarian steroids. We propose that endometrial MMP-9 activity is overall controlled by the ovarian steroids and locally adjusted through a network of modulators, including LEFTY-A.

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