Differential Regulation of Steroidogenesis by Bone Morphogenetic Proteins in Granulosa Cells: Involvement of Extracellularly Regulated Kinase Signaling and Oocyte Actions in Follicle-Stimulating Hormone-Induced Estrogen Production

Abstract

In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH-induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH-induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.

Bone morphogenetic protein 6 promotes FSH receptor and anti-Müllerian hormone mRNA expression in granulosa cells from hen prehierarchal follicles

“…For instance, BMP6 expression in sheep follicles is localized to the oocyte of primary, preantral, and antral follicles and its actions are reported to inhibit granulosa cell differentiation (Juengel et al 2006). In the rat ovary, BMP6 inhibits FSH responsiveness by suppressing adenylyl cyclase activity (Miyoshi et al 2007). Similar inhibitory effects of BMP6 on FSH responsiveness have been reported in cattle (Glister et al 2004) and pigs (Brankin et al 2005).…”

The follicular microenviroment as a predictor of pregnancy: MALDI-TOF MS lipid profile in cumulus cells

“…4 Metabolic correlation between phosphatidylserine (PS) and phosphatidylethanolamine (PE), found in the non-pregnant group, and phosphatidylcholine (PC), found in the pregnant group. PSS1 PS synthase-1; PSS2 PS synthase-2; PSD phosphatidylserine decarboxylase; PEMT phosphatidylethanolamine N-methyltransferase; ET ethanolamine transferase; EK ethanolamine kinase; CPT phosphoethanolamine cytidylyltransferase; EPT ethanolamine phosphotransferase; CT ethanolamine transferase; CK choline kinase monophosphate (cAMP) level in the female gamete, which initiates its meiotic resumption [26,29,35]. Therefore, we propose that the high PI intensity in the NP group indicates that the degradation of DAG has been not occurring or that it has been occurring at low activity, due to the reduced efficiency of meiotic resumption in this group.…”

Multiple Endocrine Regulation by Bone Morphogenetic Protein System

“…Unlike BMP-7 action, which induces granulosa cell proliferation, BMP-6 has no significant effect on granulosa cell mitosis. Interestingly, BMP-7 increases FSH-induced estradiol production whereas BMP-6 has no impact on estradiol synthesis [13]. BMP-7 action is in part mediated through a FSH receptor signaling that is independent of cAmP-PKA pathway, i.e.…”

“…BMP-7 action is in part mediated through a FSH receptor signaling that is independent of cAmP-PKA pathway, i.e. BMP-7 actions on FSH-induced estradiol production occur through suppression of ERK1/2 downstream of FSH receptor signaling [13]. Likewise, BMP-2 and -4 enhance FSH-induced p38-MAPK phosphorylation, leading to an increase of FSH-induced estradiol production [14].…”