Biological function and cellular mechanism of bone morphogenetic protein-6 in the ovary.
The process of ovarian folliculogenesis is composed of proliferation and differentiation of the constitutive cells in developing follicles. Growth factors emitted by oocytes integrate and promote this process. Growth differentiation factor-9 (GDF-9), bone morphogenetic protein (BMP)-15, and BMP-6 are oocyte-derived members of the transforming growth factor-beta superfamily. In contrast to the recent studies on GDF-9 and BMP-15, nothing is known about the biological function of BMP-6 in the ovary. Here we show that, unlike BMP-15 and GDF-9, BMP-6 lacks mitogenic activity on rat granulosa cells (GCs) and produces a marked decrease in follicle-stimulating hormone (FSH)-induced progesterone (P(4)) but not estradiol (E(2)) production, demonstrating not only the first identification of GCs as BMP-6 targets in the ovary but also its selective modulation of FSH action in steroidogenesis. This BMP-6 activity resembles BMP-15 but differs from GDF-9 activities. BMP-6 also exhibited similar action to BMP-15 by attenuating the steady state mRNA levels of FSH-induced steroidogenic acute regulatory protein (StAR) and P450 side-chain cleavage enzyme (P450scc), without affecting P450 aromatase mRNA level, supporting its differential function on FSH-regulated P(4) and E(2) production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced P(4) production and StAR and P450scc mRNA expression. BMP-6 also decreased FSH- and forskolin-stimulated cAMP production, suggesting that the underlying mechanism by which BMP-6 inhibits FSH action most likely involves the down-regulation of adenylate cyclase activity. This is clearly distinct from the mechanism of BMP-15 action, which causes the suppression of basal FSH receptor (FSH-R) expression, without affecting adenylate cyclase activity. As assumed, BMP-6 did not alter basal FSH-R mRNA levels, whereas it inhibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies provide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.
Otsuka
F
F
Department of Reproductive Medicine, University of California San Diego, School of Medicine, La Jolla, California 92093-0633, USA.
Moore
R K
RK
Shimasaki
S
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001141:Aromatase / Q000235:genetics; D055430:Bone Morphogenetic Protein 15; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology* / Q000502:physiology; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D004958:Estradiol / Q000096:biosynthesis; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006107:Granulosa Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D055429:Growth Differentiation Factor 9; D006133:Growth Substances / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D011374:Progesterone / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011962:Receptors, FSH / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D000098682:Steroidogenic Acute Regulatory Protein
C525904:Bmp15 protein, rat; C525818:Bmp6 protein, rat; D055430:Bone Morphogenetic Protein 15; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; C525899:Gdf9 protein, rat; D055429:Growth Differentiation Factor 9; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011962:Receptors, FSH; D000098682:Steroidogenic Acute Regulatory Protein; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011374:Progesterone; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D001141:Aromatase; D002786:Cholesterol Side-Chain Cleavage Enzyme