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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 10 4782-4791
Copyright © 2002 by The Endocrine Society

Original Article

Steroid and Cytokine Regulation of Matrix Metalloproteinase Expression in Endometriosis and the Establishment of Experimental Endometriosis in Nude Mice

Kaylon L. Bruner-Tran, Esther Eisenberg, Grant R. Yeaman, Ted A. Anderson, Judith McBean and Kevin G. Osteen

Women’s Reproductive Health Research Center (K.L.B.-T., E.E., G.R.Y., T.A.A., K.G.O.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and University of Vermont (J.M.), Burlington, Vermont 05401

Address all correspondence and requests for reprints to: Kevin G. Osteen, Ph.D., Women’s Reproductive Health Research Center, B-1100 Medical Center North, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville Tennessee 37232. E-mail: kevin.osteen{at}mcmail.vanderbilt.edu.

Abstract

The cyclic expression of matrix metalloproteinases (MMPs) by human endometrium has been suggested to play a role in the invasive process necessary to establish endometriosis. The ability of progesterone exposure to inhibit endometrial MMP-3 and MMP-7 expression requires the local action of TGFß and may also be linked to the local production of retinoic acid by stromal cells. A continuous expression of several MMPs in endometriotic lesions has been reported, indicating a failure of progesterone or locally produced factors to suppress these enzymes. To address cell-specific MMP regulation associated with endometriosis, we examined expression of MMP-3 and MMP-7 mRNA in eutopic endometrium and endometriotic lesions acquired during the secretory phase of the menstrual cycle. We examined the in vitro regulation of MMP-3 and MMP-7 protein in similar tissues. We also examined the in vitro regulation of MMP secretion by progesterone, retinoic acid, and TGFß in endometriosis tissues relative to the establishment of experimental disease. Our studies indicate that either eutopic or ectopic tissue from women with endometriosis exhibit patterns of altered MMP regulation in vivo. A lack of responsiveness to progesterone was demonstrated in vitro, associated with a failure to suppress MMP expression and an enhanced ability of the tissue to establish experimental endometriosis. However, in vitro treatments with retinoic acid and TGFß restored the ability of progesterone to suppress MMPs in vitro and prevented the establishment of experimental disease.




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