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Originally published In Press as doi:10.1074/jbc.M201793200 on September 4, 2002

J. Biol. Chem., Vol. 277, Issue 45, 42496-42504, November 8, 2002
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Regulation and Function of LEFTY-A/EBAF in the Human Endometrium
mRNA EXPRESSION DURING THE MENSTRUAL CYCLE, CONTROL BY PROGESTERONE, AND EFFECT ON MATRIX METALLOPROTEINASES*

Patricia B. CornetDagger §, Christine PicquetDagger , Pascale LemoineDagger , Kevin G. Osteen||, Kaylon L. Bruner-Tran||, Siamak Tabibzadeh**, Pierre J. CourtoyDagger , Yves EeckhoutDagger , Etienne MarbaixDagger Dagger Dagger , and Patrick HenrietDagger §§

From the Dagger  Cell Biology Unit, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Avenue Hippocrate, 75, B-1200 Bruxelles, Belgium, || Department of Obstetrics/Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and ** Department of Obstetrics and Gynecology and Reproductive Medicine, Stony Brook University, Stony Brook, New York 11794

The human endometrium is a unique tissue that is periodically shed during menstruation. Although overall triggered by ovarian steroids withdrawal, menstrual induction of matrix metalloproteinases (MMPs) and resulting tissue breakdown are focal responses, pointing to additional local modulators. LEFTY-A, a novel member of the transforming growth factor-beta family identified originally as an endometrial bleeding-associated factor (EBAF), is a candidate for this local control. We measured LEFTY-A and beta -ACTIN mRNA concentration during the menstrual cycle in vivo and found that their ratio was dramatically (~100-fold) increased at the perimenstrual phase. A similar increase was seen when proliferative explants were cultured for 24 h in the absence of ovarian steroids; this was followed by spontaneous production of proMMP-1, -3, and -9. Both responses were inhibited by progesterone. Moreover, addition of recombinant LEFTY-A to proliferative explants was sufficient to stimulate the expression of proMMP-3 and -7; this response was also blocked by ovarian steroids. Collectively, these data indicate that LEFTY-A may provide a crucial signal for endometrial breakdown and bleeding by triggering expression of several MMPs. Progesterone appears to exert a dual block, upstream by inhibiting LEFTY-A expression and downstream by suppressing its stimulatory effect on MMPs.

* This work was supported in part by Grant 3.4555.02 from the Belgian Fonds de la Recherche Scientifique Médicale (to E. M.), by a grant from Interuniversity Attraction Poles and Concerted Research Actions (to P. J. C.), by a grant from Organon (to E. M.), through Cooperative Agreement U54-HD-37321 as part of the Specialized Cooperative Centers Program in Reproduction Research (to K. G. O.), by a grant from Lexon, Inc., and by National Institutes of Health Grant CA8466 (to S. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Research fellow of the Belgian Fonds National de la Recherche Scientifique.

Recipient of grants from the Fonds de la Recherche Scientifique and Bourse du Patrimoine of the Université catholique de Louvain.

Dagger Dagger To whom correspondence should be addressed: Dept. of Pathology, Saint-Luc University Clinics, Avenue Hippocrate, 10, 1200 Bruxelles, Belgium. Tel.: 32-2-764-1784; Fax: 32-2-764-8924; E-mail: marbaix@cell.ucl.ac.be.

§§ Research associate of the Belgian Fonds National de la Recherche Scientifique and recipient of grants from the Fonds de la Recherche Scientifique and Bourse du Patrimoine of the Université Catholique de Louvain.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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