A novel role for bone morphogenetic proteins in the synthesis of follicle-stimulating hormone.
FSH is produced in pituitary gonadotropes as an alpha/beta heterodimer, and synthesis of the beta-subunit is the rate-limiting step in overall FSH production. Synthesis of FSHbeta can be regulated by activin and inhibin, both of which are members of the transforming growth factor-beta superfamily. Bone morphogenetic proteins (BMPs) also belong to the transforming growth factor-beta 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 FSHbeta promoter linked to a luciferase reporter gene (oFSHbetaLuc), BMP-7 or BMP-6 was found to stimulate oFSHbetaLuc expression by 6-fold. Transient expression of the oFSHbetaLuc in a transformed gonadotrope cell line, LbetaT2, 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 LbetaT2 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 oFSHbetaLuc 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 oFSHbetaLuc 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 LbetaT2 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.
Huang
H J
HJ
Department of Biochemistry, North Carolina State University, Raleigh 27695-7622, USA.
Wu
J C
JC
Su
P
P
Zhirnov
O
O
Miller
W L
WL
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000918:Antibody Specificity; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000276:immunology / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005640:Follicle Stimulating Hormone / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D037201:Follicle Stimulating Hormone, beta Subunit; D015870:Gene Expression / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011993:Recombinant Fusion Proteins; D012756:Sheep; D014162:Transfection; D016212:Transforming Growth Factor beta
D000906:Antibodies; C525817:Bmp6 protein, mouse; C525818:Bmp6 protein, rat; C525821:Bmp7 protein, rat; D055418:Bone Morphogenetic Protein 6; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D037201:Follicle Stimulating Hormone, beta Subunit; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D005640:Follicle Stimulating Hormone; D008156:Luciferases