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Department of Reproductive Medicine (M.M., S.S.H., T.B., S.S., G.F.E.), University of California, San Diego, La Jolla, California 92093; Department of Obstetrics and Gynecology (B.S.), University Clinic of Münster, Münster D-48129, Germany; Department of Obstetrics and Gynecology (A.H.), Sheba Medical Center, Tel Hashomer 52621, Israel; and Division of Reproductive Sciences (E.Y.A.), Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, Salt Lake City, Utah 84112
Address all correspondence and requests for reprints to: Gregory F. Erickson, Ph.D., Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093-0674. E-mail: gerickson{at}ucsd.edu.
Pregnancy-associated plasma protein-A (PAPP-A) is the major IGF binding protein-4 (IGFBP-4) protease in follicular fluid, consistent with its proposed role in folliculogenesis. Despite growing interest, almost nothing is known about how PAPP-A expression is regulated in any tissue. Here we show that FSH and oocytes regulate PAPP-A expression in granulosa cells (GCs). By in situ hybridization, ovary PAPP-A mRNA was markedly increased by pregnant mare serum gonadotropin treatment, and the message was localized to the membrana GCs but not cumulus GCs (CGCs) of dominant follicles. To explore the mechanism, we used primary cultures of rat GCs. Control (untreated) cells produced little or no PAPP-A spontaneously. Conversely, FSH markedly stimulated PAPP-A mRNA and protein in a dose- and time-dependent fashion. Interestingly, PAPP-A expression in isolated CGCs was also strongly induced by FSH, and the induction was inhibited by added oocytes. To investigate the nature of the inhibition, we tested the effect of oocyte-derived bone morphogenetic protein-15 (BMP-15). BMP-15 alone had no effect on basal levels of PAPP-A expression by cultures of membrana GCs or CGCs. However, BMP-15 markedly inhibited the FSH stimulation of PAPP-A production in a dose-dependent manner. The cleavage of IGFBP-4 by conditioned media from FSH-treated GCs was completely inhibited by anti-PAPP-A antibody, indicating the IGFBP-4 protease secreted by GCs is PAPP-A. These results demonstrate stimulatory and inhibitory roles for FSH and BMP-15, respectively, in regulating PAPP-A production by GCs. We propose that FSH and oocyte-derived BMP-15 form a controlling network that ensures the spatiotemporal pattern of GC PAPP-A expression in the dominant follicle.
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