PROGESTERONE REGULATES OSTEOPONTIN EXPRESSION IN HUMAN TROPHOBLASTS -A MODEL OF PARACRINE CONTROL IN THE PLACENTA

Osteopontin (OPN), a matrix glycosylated phosphoprotein, has been prop osed to play a role(s) in basic cellular processes, such as neovascula rization and tissue remodeling, which are essential to placental morph ogenesis and embryo implantation. We have shown OPN to be expressed by cytotrophoblasts of the chorionic villus, and a putative progesterone regulatory element in the OPN promoter suggests hormonal regulatory c ontrol. This led us to test the hypothesis that progesterone regulates OPN expression in human cytotrophoblasts. Cytotrophoblasts isolated f rom human placentas were treated with combinations of progesterone, RU 486, and/or aminoglutethimide, and their expression of OPN was assesse d by Northern hybridization and immunocytochemistry. The expression of OPN messenger RNA (mRNA) declined as trophoblasts aggregated, but reb ounded at later times when syncytia and mononuclear cytotrophoblasts c oexisted in culture. Progesterone increased OPN mRNA expression by agg regating mononuclear cytotrophoblasts. Aminoglutethimide suppression o f endogenous steroidogenesis by syncytiotrophoblasts inhibited OPN exp ression, whereas the addition of exogenous progesterone to cells treat ed with aminoglutethimide reversed this inhibitory effect. These obser vations were confirmed at the protein level by immunocytochemistry. Tr eatment of cytotrophoblasts with both progesterone and RU486 inhibited the up-regulatory effect on OPN mRNA associated with exposure to prog esterone alone, further confirming a direct effect of progesterone. We conclude that progesterone up-regulates OPN expression in human cytot rophoblasts, and we propose that in vivo, progesterone secretion by sy ncytiotrophoblasts regulates the expression of OPN by the underlying c ytotrophoblasts. As the receptors for OPN, alpha(v) integrins, are exp ressed by syncytiotrophoblasts, we postulate that these paracrine regu latory mechanisms contribute to the adhesive and/or signaling events b etween the two trophoblast cell types of the chorionic villus.