title: Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells.
abstract: BMPs expressed in the ovary differentially regulate steroidogenesis by granulosa cells. BMP-9, a circulating BMP, is associated with cell proliferation, apoptosis and differentiation in various tissues. However, the effects of BMP-9 on ovarian function have yet to be elucidated. Here we investigated BMP-9 actions on steroidogenesis using rat primary granulosa cells. BMP-9 potently suppressed FSH-induced progesterone production, whereas it did not affect FSH-induced estradiol production by granulosa cells. The effects of BMP-9 on FSH-induced steroidogenesis were not influenced by the presence of oocytes. FSH-induced cAMP synthesis and FSH-induced mRNA expression of steroidogenic factors, including StAR, P450scc, 3βHSD2 and FSHR, were suppressed by treatment with BMP-9. BMP-9 mRNA expression was detected in granulosa cells but not in oocytes. BMP-9 readily activated Smad1/5/8 phosphorylation and Id-1 transcription in granulosa cells. Analysis using ALK inhibitors indicated that BMP-9 actions were mediated via type-I receptors other than ALK-2, -3 and -6. Furthermore, experiments using extracellular domains (ECDs) for BMP type-I and -II receptor constructs revealed that the effects of BMP-9 were reversed by ECDs for ALK-1 and BMPRII. Thus, the functional receptors for BMP-9 in granulosa cells were most likely to be the complex of ALK-1 and BMPRII. Collectively, the results of the present study showed that BMP-9 can affect luteinization and that there are two possible sources of BMP-9, serum and granulosa cells in the ovary.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan. Electronic address: fumiotsu@md.okayama-u.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terasaka
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto-Yamauchi
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Kishio
authors.initials: K
authors.lastname: Toma
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Komatsubara
authors.affiliation: Okayama University Hospital, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D029404:Activin Receptors / Q000378:metabolism; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D006107:Granulosa Cells / Q000378:metabolism*; D055427:Growth Differentiation Factor 2 / Q000097:blood / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C526764:Acvrl1 protein, rat; D055427:Growth Differentiation Factor 2; D011374:Progesterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D029404:Activin Receptors; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Bone morphogenetic protein (BMP); Follicle-stimulating hormone (FSH); Granulosa cells; Oocyte; Steroidogenesis