175. THE ROLE OF PROPROTEIN CONVERTASE 6 DURING DECIDUALIZATION: REGULATION OF BONE MORPHOGENETIC PROTEIN 2 ACTIVATION

Abstract

Proprotein convertase 5/6 (PC6), a member of the proprotein convertase (PC) family, is a critical endometrial factor for implantation. PC6 is up-regulated in the endometrium specifically at implantation in association with epithelial differentiation (in human and monkey) and stromal cell decidualization (in the mouse, human and monkey). PC6 is the only PC member that was significantly up-regulated during decidualization. Knockdown of PC6 inhibits decidualization. PCs function by converting a range of important precursor proteins into their bioactive forms. One group of such proteins is the transforming growth factor beta (TGF-beta) superfamily proteins. They are first synthesized as larger biologically inactive precursors, and then are processed by PCs into their active forms. Bone morphogenetic protein 2 (BMP2) is a TGF-beta superfamily member and demonstrated to be essential for decidualization. We hypothesized that BMP2 is one of the proteins that PC6 activates during decidualization. Freshly isolated stromal cells from human endometrium were decidualized in culture with and without inhibition of PC6 activity. The full-length (precursor, non-active) and processed (activated) forms of BMP2 were determined in cellular lysates and media. The precursor form of BMP2 was reduced whereas the active form was increased during decidualization. Inhibition of PC6 activity inhibited decidualization, and this inhibition was accompanied by a total inhibition of the production of active BMP2. To further confirm the role of PC6 in activating BMP2 in decidualization, active BMP2 was added into cells and the decidualization arrest caused by PC6 inhibition was partially rescued. This study demonstrated that PC6 regulates decidualization by activating molecules such as BMP2 that are essential for decidualization.