Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells

• Published in: The Journal of steroid biochemistry and molecular biology 2015-03, Vol.147, p.85-91
• Main Authors: Hosoya, Takeshi, Otsuka, Fumio, Nakamura, Eri, Terasaka, Tomohiro, Inagaki, Kenichi, Tsukamoto-Yamauchi, Naoko, Hara, Takayuki, Toma, Kishio, Komatsubara, Motoshi, Makino, Hirofumi
• Format: Article
• Language: English
• Subjects: Activin Receptors - metabolism; Animals; Bone morphogenetic protein (BMP); Bone Morphogenetic Protein Receptors, Type II - metabolism; Cells, Cultured; Cyclic AMP - metabolism; Estradiol - metabolism; Female; Follicle Stimulating Hormone - metabolism; Follicle-stimulating hormone (FSH); Granulosa cells; Granulosa Cells - metabolism; Growth Differentiation Factor 2 - blood; Growth Differentiation Factor 2 - metabolism; Oocyte; Oocytes - metabolism; Ovary - cytology; Ovary - metabolism; Progesterone - metabolism; Rats; Rats, Sprague-Dawley; Steroidogenesis
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2014.12.007

•BMP-9 suppressed FSH-induced progesterone production by granulosa cells regardless of oocyte actions.•FSH-induced cAMP synthesis and steroidogenic factor mRNAs were suppressed by BMP-9.•Functional receptors for BMP-9 were the complex of ALK-1/BMPRII expressed on granulosa cells.•BMP-9 contributes to luteinizing inhibition as a circulating factor during folliculogenesis. 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.