This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matsui, M. Articles by Erickson, G. F. Search for Related Content PubMed PubMed Citation Articles by Matsui, M. Articles by Erickson, G. F.

Pregnancy-Associated Plasma Protein-A Production in Rat Granulosa Cells: Stimulation by Follicle-Stimulating Hormone and Inhibition by the Oocyte-Derived Bone Morphogenetic Protein-15

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.

This article has been cited by other articles:

				H. E. McMahon, O. Hashimoto, P. L. Mellon, and S. Shimasaki Oocyte-Specific Overexpression of Mouse Bone Morphogenetic Protein-15 Leads to Accelerated Folliculogenesis and an Early Onset of Acyclicity in Transgenic Mice Endocrinology, June 1, 2008; 149(6): 2807 - 2815. [Abstract] [Full Text] [PDF]

				Y.-T. Wu, L. Tang, J. Cai, X.-E Lu, J. Xu, X.-M. Zhu, Q. Luo, and H.-F. Huang High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development Hum. Reprod., June 1, 2007; 22(6): 1526 - 1531. [Abstract] [Full Text] [PDF]

				I Demeestere, J Centner, C Gervy, Y Englert, and A Delbaere Impact of various endocrine and paracrine factors on in vitro culture of preantral follicles in rodents Reproduction, August 1, 2005; 130(2): 147 - 156. [Abstract] [Full Text] [PDF]