This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jaatinen, R. Articles by Ritvos, O. Search for Related Content PubMed PubMed Citation Articles by Jaatinen, R. Articles by Ritvos, O.

Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin ß_B-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells

Program for Developmental and Reproductive Biology, Biomedicum Helsinki (J.B., L.D., O.R.), and Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki (R.J., J.B., K.H., O.R.), and Hospital of Children and Adolescents, Helsinki University Central Hospital (T.R., L.D.), 00014 Helsinki, Finland; and School of Biological and Molecular Sciences (N.G.), Oxford Brookes University, Headington, Oxford OX3 0BP, United Kingdom

Address all correspondence and requests for reprints to: Dr. Olli Ritvos, Biomedicum Helsinki, Room C502b, P.O. Box 63, Haartmaninkatu 8, 00014 University of Helsinki, Finland. E-mail: . olli.ritvos{at}helsinki.fi

Abstract

During the human menstrual cycle the circulating levels of inhibin B, a dimer of inhibin - and ß_B-subunits, fluctuate in a fashion distinct from that of inhibin A, the -ß_A-subunit dimer. This suggests that human inhibin subunits are each regulated in a distinct manner in human ovarian granulosa cells by endocrine and local factors. We have previously shown using cultures of human granulosa-luteal (hGL) cells that gonadotropins stimulate the steady state mRNA levels of inhibin - and ß_A-subunits, but not those of the ß_B-subunit, which, on the other hand, are up-regulated by, for instance, activin and TGFß. We recently identified the TGFß gene family member bone morphogenetic protein-3 (BMP-3) as a granulosa cell-derived growth factor, but whether BMP-3 or other structurally related BMPs regulate human granulosa cell inhibin production is not known. We show here that hGL cells express mRNAs for distinct serine/threonine kinase receptors (BMP-RIA and BMP-RII) and Smad signaling proteins (Smad1, Smad4, and Smad5) involved in the mediation of cellular effects of BMPs. Subsequently, we determined in hGL cell cultures the effects of distinct members of the BMP family previously found to be expressed in mammalian ovaries. Recombinant BMP-2 induces potently in a time- and concentration-dependent manner the expression of the inhibin ß_B-subunit mRNAs in hGL cells without affecting the levels of - or ß_A-subunit mRNAs. BMP-6 has a similar, but weaker, effect than BMP-2, whereas BMP-3 and its close homolog, BMP-3b (also known as growth differentiation factor-10) had no effect on inhibin subunit mRNA expression. hCG treatment of hGL cells was previously shown to abolish the stimulatory effect of activin on ß_B-subunit mRNA levels, and here hCG is also shown to suppress the effect of BMP-2. Furthermore, BMP-2 stimulates hGL cell secreted dimeric inhibin B levels in a concentration-dependent manner. Depending on the experiment, maximal increases in inhibin B levels of 6- to 28-fold above basal levels were detected during a 72-h culture period. We conclude that activation of the BMP-signaling pathway in hGL cells stimulates inhibin ß_B-subunit mRNA levels and leads at the protein level to a dramatic stimulation of secreted inhibin B dimers. Our results are consistent with the suggestion that in addition to the distinct activin- and TGFß-activated signaling pathways, the BMP-activated pathway is likely to be implicated in the complex regulation of inhibins in the human ovary.

This article has been cited by other articles:

				F.-T. Shi, A. P. Cheung, and P. C. K. Leung Growth Differentiation Factor 9 Enhances Activin A-Induced Inhibin B Production in Human Granulosa Cells Endocrinology, August 1, 2009; 150(8): 3540 - 3546. [Abstract] [Full Text] [PDF]

				K. Inagaki, F. Otsuka, T. Miyoshi, M. Yamashita, M. Takahashi, J. Goto, J. Suzuki, and H. Makino p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4 Endocrinology, April 1, 2009; 150(4): 1921 - 1930. [Abstract] [Full Text] [PDF]

				J. L. Kipp, S. M. Kilen, T. K. Woodruff, and K. E. Mayo Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary J. Biol. Chem., December 14, 2007; 282(50): 36755 - 36765. [Abstract] [Full Text] [PDF]

				S. L Al-Musawi, R. T Gladwell, and P. G Knight Bone morphogenetic protein-6 enhances gonadotrophin-dependent progesterone and inhibin secretion and expression of mRNA transcripts encoding gonadotrophin receptors and inhibin/activin subunits in chicken granulosa cells Reproduction, August 1, 2007; 134(2): 293 - 306. [Abstract] [Full Text] [PDF]

				K. B Lee, V. Khivansara, M. M Santos, P. Lamba, T. Yuen, S. C Sealfon, and D. J Bernard Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone {beta} subunit transcription J. Mol. Endocrinol., February 1, 2007; 38(2): 315 - 330. [Abstract] [Full Text] [PDF]

				L. Bodin, E. Di Pasquale, S. Fabre, M. Bontoux, P. Monget, L. Persani, and P. Mulsant A Novel Mutation in the Bone Morphogenetic Protein 15 Gene Causing Defective Protein Secretion Is Associated with Both Increased Ovulation Rate and Sterility in Lacaune Sheep Endocrinology, January 1, 2007; 148(1): 393 - 400. [Abstract] [Full Text] [PDF]

				P. G Knight and C. Glister TGF-{beta} superfamily members and ovarian follicle development. Reproduction, August 1, 2006; 132(2): 191 - 206. [Abstract] [Full Text] [PDF]

				C. Glister, S. L. Richards, and P. G. Knight Bone Morphogenetic Proteins (BMP) -4, -6, and -7 Potently Suppress Basal and Luteinizing Hormone-Induced Androgen Production by Bovine Theca Interna Cells in Primary Culture: Could Ovarian Hyperandrogenic Dysfunction Be Caused by a Defect in Thecal BMP Signaling? Endocrinology, April 1, 2005; 146(4): 1883 - 1892. [Abstract] [Full Text] [PDF]

				J.L. Juengel and K.P. McNatty The role of proteins of the transforming growth factor-{beta} superfamily in the intraovarian regulation of follicular development Hum. Reprod. Update, March 1, 2005; 11(2): 144 - 161. [Abstract] [Full Text] [PDF]

				N. Kaivo-Oja, D. G. Mottershead, S. Mazerbourg, S. Myllymaa, S. Duprat, R. B. Gilchrist, N. P. Groome, A. J. Hsueh, and O. Ritvos Adenoviral Gene Transfer Allows Smad-Responsive Gene Promoter Analyses and Delineation of Type I Receptor Usage of Transforming Growth Factor-{beta} Family Ligands in Cultured Human Granulosa Luteal Cells J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 271 - 278. [Abstract] [Full Text] [PDF]

				S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson The Bone Morphogenetic Protein System In Mammalian Reproduction Endocr. Rev., February 1, 2004; 25(1): 72 - 101. [Abstract] [Full Text] [PDF]

				C. Glister, C F. Kemp, and P. G Knight Bone morphogenetic protein (BMP) ligands and receptors in bovine ovarian follicle cells: actions of BMP-4, -6 and -7 on granulosa cells and differential modulation of Smad-1 phosphorylation by follistatin Reproduction, February 1, 2004; 127(2): 239 - 254. [Abstract] [Full Text] [PDF]

				E. E. Nilsson and M. K. Skinner Bone Morphogenetic Protein-4 Acts as an Ovarian Follicle Survival Factor and Promotes Primordial Follicle Development Biol Reprod, October 1, 2003; 69(4): 1265 - 1272. [Abstract] [Full Text] [PDF]

				E. Wiater and W. Vale Inhibin Is an Antagonist of Bone Morphogenetic Protein Signaling J. Biol. Chem., February 28, 2003; 278(10): 7934 - 7941. [Abstract] [Full Text] [PDF]

				N. Kaivo-Oja, J. Bondestam, M. Kamarainen, J. Koskimies, U. Vitt, M. Cranfield, K. Vuojolainen, J. P. Kallio, V. M. Olkkonen, M. Hayashi, et al. Growth Differentiation Factor-9 Induces Smad2 Activation and Inhibin B Production in Cultured Human Granulosa-Luteal Cells J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 755 - 762. [Abstract] [Full Text] [PDF]

				R. K. Moore, F. Otsuka, and S. Shimasaki Molecular Basis of Bone Morphogenetic Protein-15 Signaling in Granulosa Cells J. Biol. Chem., January 3, 2003; 278(1): 304 - 310. [Abstract] [Full Text] [PDF]

				J.-S. Roh, J. Bondestam, S. Mazerbourg, N. Kaivo-Oja, N. Groome, O. Ritvos, and A. J. W. Hsueh Growth Differentiation Factor-9 Stimulates Inhibin Production and Activates Smad2 in Cultured Rat Granulosa Cells Endocrinology, January 1, 2003; 144(1): 172 - 178. [Abstract] [Full Text] [PDF]

				C. Welt, Y. Sidis, H. Keutmann, and A. Schneyer Activins, Inhibins, and Follistatins: From Endocrinology to Signaling. A Paradigm for the New Millennium Experimental Biology and Medicine, October 1, 2002; 227(9): 724 - 752. [Abstract] [Full Text] [PDF]