title: Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells.
abstract: Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules in regulating ovarian physiology, with different BMPs having differential actions in FSH-induced estradiol production. To identify the roles of oocyte factors that modulate steroidogenesis controlled by BMPs, we here investigated the effects of FGF-8 in rat granulosa/oocyte co-cultures. FGF-8 potently suppressed FSH-induced estradiol production, but did not affect cAMP-induced estradiol produced by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH and forskolin. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMP-2, -4, -6 or -7. In the presence of FGF-8, BMPs suppressed FSH-induced progesterone by reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH receptor signaling. Notably, FGF-8-induced ERK and SAPK/JNK phosphorylation in granulosa cells, in which ERK activation was further enhanced by FSH and oocytes. Inhibition of ERK and SAPK/JNK reduced FSH-induced progesterone and cAMP levels, suggesting that the activation of these pathways enhances FSH-induced cAMP signaling. In addition, ERK inhibition upregulated FSH-induced estradiol synthesis, indicating that ERK pathway is also involved in suppressing aromatase activity in granulosa cells. Interestingly, FGF-8 enhanced BMP-induced Smad1/5/8 and Id-1-promoter activities with decreased expression of Smad6/7. Since the SAPK/JNK inhibitor inhibited FGF-8 effects in upregulating Id-1 transcription, SAPK/JNK appears to be involved in the mechanism by which FGF-8 enhances BMP-Smad signaling. Furthermore, in the presence of oocytes, the inhibition of endogenous FGF receptor signaling suppressed FSH- and forskolin-induced progesterone and cAMP, showing that endogenous FGF system is involved in activation of FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK. Thus, the oocyte factor, FGF-8, not only suppresses FSH-induced estradiol production by activating ERK, but also enhances BMP-Smad signaling in granulosa cells. This interaction between FGF-8 and BMPs may play a key role in regulating steroidogenesis through oocyte-granulosa cell communication.
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: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Misuzu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Eri
authors.initials: E
authors.lastname: Nakamura
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000494:pharmacology / Q000502:physiology*; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D019485:Bone Morphogenetic Proteins; D017468:Receptors, Fibroblast Growth Factor; D013256:Steroids; D051524:Fibroblast Growth Factor 8; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP