Abstract: 578

PROGESTERONE REGULATION OF ENDOMETRIAL MMP-3 EXPRESSION REQUIRES THE COOPERATIVE ACTION OF TRANSFORMING GROWTH FACTOR- AND RETINOIC ACID.

Kaylon Bruner^{1 *}, David Ong² , Esther Eisenberg¹ , Kevin Osteen^{1 *}
Dept of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN ¹
Dept of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN ²

The human menstrual cycle is regulated by the ovarian steroids estradiol and progesterone. Local factors also act in concert with steroids to coordinate endometrial growth, remodeling and breakdown. A key component of tissue restructuring are matrix metalloproteinases (MMPs), secreted enzymes which mediate extracellular matrix breakdown. Several MMPs of the stromelysin family, including MMP-3 and MMP-7, are expressed during endometrial growth and breakdown, but are absent during the progesterone-dominated secretory phase. Suppression of MMP-7 by progesterone is linked to increases in the local production of transforming growth factor-2 (TGF-2), however, in vitro studies indicate that an additional factor is required for suppression of MMP-3. In the present study, we examined the potential role of local retinoic acid (RA) synthesis in the regulation of endometrial MMP-3 expression. Using retinol precursor and HPLC analysis, we determined that endometrial stromal cells synthesize only low levels of RA following estradiol exposure. However, in an in vitro model of stromal cell decidualization, progesterone exposure increased RA synthesis 200-300 fold. Western analysis indicated that treatments with RA (10 nM), in the absence of progesterone, suppressed MMP-3 secretion by either isolated stromal cells or endometrial organ cultures. Additionally, RA treatments increase TGF-2 expression in endometrial organ cultures and RA-mediated MMP-3 suppression could be blocked by addition of anti-TGF- antibody. We conclude that progesterone acts in concert with local production of both RA and TGF- to regulate endometrial MMP-3 expression. Understanding cell-cell communication relative to regulation of MMPs will provide insight into abberant expression of these enzymes in uterine disease. Supported by NIH Grants HD28128 and HD36707.

    This abstract is being presented on Tuesday, August 3 at 4:30 PM at Todd 130.