This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited 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 Huang, H.-J. Articles by Miller, W. L. Search for Related Content PubMed PubMed Citation Articles by Huang, H.-J. Articles by Miller, W. L.

A Novel Role for Bone Morphogenetic Proteins in the Synthesis of Follicle-Stimulating Hormone¹

Department of Biochemistry, North Carolina State University, Raleigh, North Carolina 27695-7622

Address all correspondence and requests for reprints to: Dr. William L. Miller, Department of Biochemistry, Box 7622, North Carolina State University, Raleigh, North Carolina 27695-7622. E-mail: wlmiller{at}bchserver.bch.ncsu.edu

FSH is produced in pituitary gonadotropes as an /ß heterodimer, and synthesis of the ß-subunit is the rate-limiting step in overall FSH production. Synthesis of FSHß can be regulated by activin and inhibin, both of which are members of the transforming growth factor-ß superfamily. Bone morphogenetic proteins (BMPs) also belong to the transforming growth factor-ß family and are multifunctional growth factors involved in many aspects of tissue development and morphogenesis, including regulation of FSH action in the ovary. Here we report a novel function for BMP-7 and BMP-6 in regulating FSH synthesis in the pituitary. Using primary pituitary cell cultures derived from transgenic mice that carry the ovine FSHß promoter linked to a luciferase reporter gene (oFSHßLuc), BMP-7 or BMP-6 was found to stimulate oFSHßLuc expression by 6-fold. Transient expression of the oFSHßLuc in a transformed gonadotrope cell line, LßT2, was induced 4-fold by BMP-7 or BMP-6 treatment. More importantly, BMP-7 and BMP-6 increased endogenous FSH secretion by 10- and 14-fold, respectively, from LßT2 cells, demonstrating for the first time that a functional signaling BMP system is present in gonadotropes. Two bioneutralizing antibodies to BMP-7, which cross-react with BMP-6, but not with activin A, decreased basal oFSHßLuc expression and FSH secretion from transgenic mouse pituitary cultures by 83–88% and 47–48%, respectively, suggesting an autocrine or paracrine role for BMP-7 or BMP-6 in FSH synthesis. Neither bioneutralizing antibody to activin A or activin B decreased basal oFSHßLuc expression or mouse FSH secretion significantly. Dose-dependent inhibition of FSH synthesis by anti-BMP7 was also observed in rat and sheep pituitary cultures. These results combined with the fact that the messenger RNAs for BMP-7 and BMP-6 were detected in mouse pituitaries and LßT2 cells indicate that BMP-7 and/or BMP-6 can function as FSH stimulators and may be significant physiological factors maintaining basal FSH expression in vivo.

This article has been cited by other articles:

				L Nicol, M-O Faure, J R McNeilly, J Fontaine, C Taragnat, and A S McNeilly Bone morphogenetic protein-4 interacts with activin and GnRH to modulate gonadotrophin secretion in L{beta}T2 gonadotrophs J. Endocrinol., March 1, 2008; 196(3): 497 - 507. [Abstract] [Full Text] [PDF]

				J. M Young, J. L Juengel, K. G Dodds, M. Laird, P. K Dearden, A. S McNeilly, K. P McNatty, and T. Wilson The activin receptor-like kinase 6 Booroola mutation enhances suppressive effects of bone morphogenetic protein 2 (BMP2), BMP4, BMP6 and growth and differentiation factor-9 on FSH release from ovine primary pituitary cell cultures J. Endocrinol., February 1, 2008; 196(2): 251 - 261. [Abstract] [Full Text] [PDF]

				G. F Y Cheng, C.-W. Yuen, and W. Ge Evidence for the existence of a local activin follistatin negative feedback loop in the goldfish pituitary and its regulation by activin and gonadal steroids J. Endocrinol., December 1, 2007; 195(3): 373 - 384. [Abstract] [Full Text] [PDF]

				P. Su, F. Shafiee-Kermani, A. J. Gore, J. Jia, J. C. Wu, and W. L. Miller Expression and Regulation of the {beta}-Subunit of Ovine Follicle-Stimulating Hormone Relies Heavily on a Promoter Sequence Likely to Bind Smad-Associated Proteins Endocrinology, September 1, 2007; 148(9): 4500 - 4508. [Abstract] [Full Text] [PDF]

				M. Takeda, F. Otsuka, H. Otani, K. Inagaki, T. Miyoshi, J. Suzuki, Y. Mimura, T. Ogura, and H. Makino Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope L{beta}T2 cells J. Endocrinol., July 1, 2007; 194(1): 87 - 99. [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]

				N. Safwat, J. Ninomiya-Tsuji, A. J. Gore, and W. L. Miller Transforming Growth Factor {beta}-Activated Kinase 1 Is a Key Mediator of Ovine Follicle-Stimulating Hormone {beta}-Subunit Expression Endocrinology, November 1, 2005; 146(11): 4814 - 4824. [Abstract] [Full Text] [PDF]

				P. Su, J. C. Wu, J. R. Sommer, A. J. Gore, R. M. Petters, and W. L. Miller Conditional Induction of Ovulation in Mice Biol Reprod, October 1, 2005; 73(4): 681 - 687. [Abstract] [Full Text] [PDF]

				Y. Xia, Y. Sidis, A. Mukherjee, T. A. Samad, G. Brenner, C. J. Woolf, H. Y. Lin, and A. Schneyer Localization and Action of Dragon (Repulsive Guidance Molecule b), a Novel Bone Morphogenetic Protein Coreceptor, throughout the Reproductive Axis Endocrinology, August 1, 2005; 146(8): 3614 - 3621. [Abstract] [Full Text] [PDF]

				M-O Faure, L Nicol, S Fabre, J Fontaine, N Mohoric, A McNeilly, and C Taragnat BMP-4 inhibits follicle-stimulating hormone secretion in ewe pituitary J. Endocrinol., July 1, 2005; 186(1): 109 - 121. [Abstract] [Full Text] [PDF]

				J. C. Wu, P. Su, N. W. Safwat, J. Sebastian, and W. L. Miller Rapid, Efficient Isolation of Murine Gonadotropes and Their Use in Revealing Control of Follicle-Stimulating Hormone by Paracrine Pituitary Factors Endocrinology, December 1, 2004; 145(12): 5832 - 5839. [Abstract] [Full Text] [PDF]

				J. S. Bailey, N. Rave-Harel, S. M. McGillivray, D. Coss, and P. L. Mellon Activin Regulation of the Follicle-Stimulating Hormone {beta}-Subunit Gene Involves Smads and the TALE Homeodomain Proteins Pbx1 and Prep1 Mol. Endocrinol., May 1, 2004; 18(5): 1158 - 1170. [Abstract] [Full Text] [PDF]

				D. J. Bernard Both SMAD2 and SMAD3 Mediate Activin-Stimulated Expression of the Follicle-Stimulating Hormone {beta} Subunit in Mouse Gonadotrope Cells Mol. Endocrinol., March 1, 2004; 18(3): 606 - 623. [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]

				J. Suzuki, F. Otsuka, K. Inagaki, M. Takeda, T. Ogura, and H. Makino Novel Action of Activin and Bone Morphogenetic Protein in Regulating Aldosterone Production by Human Adrenocortical Cells Endocrinology, February 1, 2004; 145(2): 639 - 649. [Abstract] [Full Text] [PDF]

				H. T. Keutmann, A. L. Schneyer, and Y. Sidis The Role of Follistatin Domains in Follistatin Biological Action Mol. Endocrinol., January 1, 2004; 18(1): 228 - 240. [Abstract] [Full Text] [PDF]

				G. Y. Bedecarrats, F. H. O'Neill, E. R. Norwitz, U. B. Kaiser, and J. Teixeira Regulation of gonadotropin gene expression by Mullerian inhibiting substance PNAS, August 5, 2003; 100(16): 9348 - 9353. [Abstract] [Full Text] [PDF]

				A. Schneyer, A. Schoen, A. Quigg, and Y. Sidis Differential Binding and Neutralization of Activins A and B by Follistatin and Follistatin Like-3 (FSTL-3/FSRP/FLRG) Endocrinology, May 1, 2003; 144(5): 1671 - 1674. [Abstract] [Full Text] [PDF]

				M. I. Suszko, D. J. Lo, H. Suh, S. A. Camper, and T. K. Woodruff Regulation of the Rat Follicle-Stimulating Hormone {beta}-Subunit Promoter by Activin Mol. Endocrinol., March 1, 2003; 17(3): 318 - 332. [Abstract] [Full Text] [PDF]

				J. L. Juengel, N. L. Hudson, D. A. Heath, P. Smith, K. L. Reader, S. B. Lawrence, A. R. O'Connell, M. P.E. Laitinen, M. Cranfield, N. P. Groome, et al. Growth Differentiation Factor 9 and Bone Morphogenetic Protein 15 Are Essential for Ovarian Follicular Development in Sheep Biol Reprod, December 1, 2002; 67(6): 1777 - 1789. [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]

				M. M. Zakaria, K.-H. Jeong, C. Lacza, and U. B. Kaiser Pituitary Homeobox 1 Activates the Rat FSH{beta} (rFSH{beta}) Gene through Both Direct and Indirect Interactions with the rFSH{beta} Gene Promoter Mol. Endocrinol., August 1, 2002; 16(8): 1840 - 1852. [Abstract] [Full Text] [PDF]

				V. Padmanabhan, D. Battaglia, M. B. Brown, F. J. Karsch, J. S. Lee, W. Pan, D. J. Phillips, and J. Van Cleeff Neuroendocrine Control of Follicle-Stimulating Hormone (FSH) Secretion: II. Is Follistatin-Induced Suppression of FSH Secretion Mediated via Changes in Activin Availability and Does It Involve Changes in Gonadotropin-Releasing Hormone Secretion? Biol Reprod, May 1, 2002; 66(5): 1395 - 1402. [Abstract] [Full Text]

				E. R. Norwitz, S. Xu, K.-H. Jeong, G. Y. Bedecarrats, L. D. Winebrenner, W. W. Chin, and U. B. Kaiser Activin A Augments GnRH-Mediated Transcriptional Activation of the Mouse GnRH Receptor Gene Endocrinology, March 1, 2002; 143(3): 985 - 997. [Abstract] [Full Text]