Endocrine Abstracts

Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules as a luteinizing factor but BMPs have differential actions in FSH-induced estradiol production in a ligand-dependent manner. We recently reported the presence of oocyte–granulosa cell communication through BMP actions by regulating MAPK. To approach the 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, while it did not affect cAMP-induced estradiol levels by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMPs. However, in the presence of FGF-8, BMPs significantly suppressed FSH-induced progesterone with reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH-R signaling. Notably, FGF-8 induced ERK and SAPK/JNK phosphorylation in granulosa cells, which was further enhanced by FSH. Inhibitions of ERK and SAPK/JNK commonly 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, suggesting 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 a SAPK/JNK inhibitor restored the FGF-8 effects upregulating Id-1-Luc activity, 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-R signaling by SU5402 suppressed FSH-induced progesterone and cAMP, implying that endogenous FGF-8 activates FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK pathways. Thus, an oocyte factor FGF-8 not only suppresses FSH-induced estradiol production by activating MAPK, 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.