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

Endocrinology. 2007 Jan;148(1):337-45. doi: 10.1210/en.2006-0966. Epub 2006 Sep 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins / metabolism*
  • Bone Morphogenetic Proteins / pharmacology
  • Cell Communication / drug effects
  • Cell Communication / physiology
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Estrogens / metabolism*
  • Female
  • Follicle Stimulating Hormone / metabolism*
  • Follicle Stimulating Hormone / pharmacology
  • Granulosa Cells / cytology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Oocytes / cytology
  • Oocytes / drug effects
  • Oocytes / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / pharmacology

Substances

  • Bmp6 protein, rat
  • Bmp7 protein, rat
  • Bone Morphogenetic Protein 6
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Estrogens
  • Transforming Growth Factor beta
  • Follicle Stimulating Hormone
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3