Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary

Fumio Otsuka, R. Kelly Moore, Shunichi Shimasaki

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

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-β 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 (P4) but not estradiol (E2) 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 P4 and E2 production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced p4 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 in. hibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies pro. vide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.

Original languageEnglish
Pages (from-to)32889-32895
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number35
DOIs
Publication statusPublished - Aug 31 2001
Externally publishedYes

Fingerprint

Bone Morphogenetic Protein 6
Bone Morphogenetic Protein 15
Follicle Stimulating Hormone
Ovary
Growth Differentiation Factor 9
Colforsin
Messenger RNA
8-Bromo Cyclic Adenosine Monophosphate
Granulosa Cells
Adenylyl Cyclases
Oocytes
FSH Receptors
Aromatase
Transforming Growth Factors
Enzymes
Progesterone
Rats

ASJC Scopus subject areas

  • Biochemistry

Cite this

Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary. / Otsuka, Fumio; Moore, R. Kelly; Shimasaki, Shunichi.

In: Journal of Biological Chemistry, Vol. 276, No. 35, 31.08.2001, p. 32889-32895.

Research output: Contribution to journalArticle

Otsuka, Fumio ; Moore, R. Kelly ; Shimasaki, Shunichi. / Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 35. pp. 32889-32895.
@article{5bfe57efbf1544e6a44ef1bb27831a75,
title = "Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary",
abstract = "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-β 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 (P4) but not estradiol (E2) 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 P4 and E2 production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced p4 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 in. hibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies pro. vide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.",
author = "Fumio Otsuka and Moore, {R. Kelly} and Shunichi Shimasaki",
year = "2001",
month = "8",
day = "31",
doi = "10.1074/jbc.M103212200",
language = "English",
volume = "276",
pages = "32889--32895",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "35",

}

TY - JOUR

T1 - Biological Function and Cellular Mechanism of Bone Morphogenetic Protein-6 in the Ovary

AU - Otsuka, Fumio

AU - Moore, R. Kelly

AU - Shimasaki, Shunichi

PY - 2001/8/31

Y1 - 2001/8/31

N2 - 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-β 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 (P4) but not estradiol (E2) 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 P4 and E2 production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced p4 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 in. hibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies pro. vide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.

AB - 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-β 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 (P4) but not estradiol (E2) 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 P4 and E2 production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced p4 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 in. hibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies pro. vide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.

UR - http://www.scopus.com/inward/record.url?scp=0035980024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035980024&partnerID=8YFLogxK

U2 - 10.1074/jbc.M103212200

DO - 10.1074/jbc.M103212200

M3 - Article

C2 - 11447221

AN - SCOPUS:0035980024

VL - 276

SP - 32889

EP - 32895

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 35

ER -