title: 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.
abstract: 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.
authors.affiliation: Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093-0674, USA.
authors.forename: Motozumi
authors.initials: M
authors.lastname: Matsui
authors.forename: Barbara
authors.initials: B
authors.lastname: Sonntag
authors.forename: Seong Soo
authors.initials: SS
authors.lastname: Hwang
authors.forename: Tara
authors.initials: T
authors.lastname: Byerly
authors.forename: Ariel
authors.initials: A
authors.lastname: Hourvitz
authors.forename: Eli Y
authors.initials: EY
authors.lastname: Adashi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shimasaki
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Erickson
mesh_terms: D000818:Animals; D055430:Bone Morphogenetic Protein 15; D002478:Cells, Cultured; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006064:Gonadotropins, Equine / Q000494:pharmacology; D006107:Granulosa Cells / Q000378:metabolism*; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D010053:Ovary / Q000378:metabolism; D011266:Pregnancy-Associated Plasma Protein-A / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C525904:Bmp15 protein, rat; D055430:Bone Morphogenetic Protein 15; C525899:Gdf9 protein, rat; D006064:Gonadotropins, Equine; D055429:Growth Differentiation Factor 9; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D005640:Follicle Stimulating Hormone; D011266:Pregnancy-Associated Plasma Protein-A