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Extracellular Matrix Metalloproteinase Inducer Regulates Metalloproteinases in Human Uterine Endometrium

Department of Animal Sciences (A.G.B., R.A.N.), Urbana, Illinois 61801; Department of Obstetrics and Gynecology, University of Illinois (A.T.F.), Chicago, Illinois 60612; Department of Anatomy and Cell Biology, Tufts University (H.G.), Boston, Massachusetts 02111; Department of Cell Biology and Anatomy, Medical University of South Carolina (B.P.T.), Charleston, South Carolina 29425; and Department of Reproductive Endocrinology, Greenville Hospital System (B.A.L.), Greenville, South Carolina 29605

Address all correspondence and requests for reprints to: Dr. Romana Nowak, University of Illinois, 1207 West Gregory Drive, Urbana, Illinois 61801. E-mail: ranowak{at}uiuc.edu.

Context: Endometrial remodeling occurs during each menstrual cycle in women and also during the establishment of endometriosis. Both processes involve the production of metalloproteinases (MMPs) by uterine endometrial cells.

Objective: The objective of this study was to determine whether tissue remodeling and endometrial invasion involve activation of MMPs by extracellular matrix metalloproteinase inducer (EMMPRIN).

Main Outcome Measures: EMMPRIN expression was examined by immunohistochemistry and real-time PCR in ectopic and eutopic endometria. For functional assays, human uterine fibroblasts were treated in the absence or presence of IL-1ß (10 ng/ml) or purified native EMMPRIN (0.5 or 1 µg/ml) for 24 h. Cellular RNA and conditioned medium were assayed by real-time PCR or immunoblotting.

Results: EMMPRIN protein localized to epithelial and fibroblast cells of eutopic and ectopic endometria. The pattern of localization was regulated by ovarian hormones. EMMPRIN mRNA levels varied throughout the menstrual cycle in parallel with the cyclic changes in estradiol. EMMPRIN treatment (0.5 µg/ml) of human uterine fibroblast cells stimulated MMP-1 (5.23-fold) and MMP-2 (8.55-fold), but not MMP-3, mRNA levels over levels in control cells (P < 0.05). EMMPRIN treatment (1 µg/ml) stimulated endogenous EMMPRIN (1.6-fold) mRNA levels (P > 0.05). IL-1ß stimulated MMP-1 (5.6-fold), MMP-2 (2.8-fold), and MMP-3 (75-fold) gene expression, but not EMMPRIN, over levels in control cells (P < 0.05). Both EMMPRIN and IL-1ß treatments stimulated MMP-1, -2, and -3, but not EMMPRIN protein secretion, with 0.5 µg/ml producing the greatest response.

Conclusions: The ability of EMMPRIN to stimulate MMP secretion by endometrial fibroblasts indicates its potential role in uterine remodeling and the pathogenesis of endometriosis.