|Figure 1. BMP-7 or BMP-6 can function as autocrine or paracrine stimulators of FSH synthesis in pituitary gonadotropes.|
Follicle-stimulating hormone (FSH) is produced as an alpha/beta heterodimer within pituitary gonadotropes. Synthesis of the beta-subunit of FSH is the rate-limiting step in its overall production. Members of the TGF-beta superfamily have been shown to regulate the synthesis of FSH beta. Activin, for example, stimulates secretion of FSH by increasing FSH beta gene expression at the transcriptional level.1,2 Inhibin, although structurally similar to activin, is a negative regulator of FSH beta gene expression.3 Additional evidence that supports the influence of activin and inhibin on FSH synthesis has been generated with knockout mice. Mice lacking the Activin ActRII receptors have significantly reduced serum FSH levels, thus emphasizing the importance of activin in inducing FSH expression.4 Activin /Inhibin betaB knockout mice, by contrast, demonstrate slightly elevated levels of serum FSH.4 Bone morphogenetic protein (BMP)-7, another TGF-beta superfamily member, can bind ActRII and transduce an activin-like signal, suggesting the possibility that it may serve as an alternative ligand for induction of FSH beta in the absence of activin. 5 Levels of BMP-7 were not measured, however, in the knockout mice studies previously listed.
In a recent study by Huang et al.,6 a functional BMP system is identified within gonadotropes demonstrating that BMPs play a novel role in regulating FSH synthesis in the pituitary. Transient expression of oFSH beta Luc (ovine FSH beta promoter linked to a luciferase reporter gene) in a transformed gonadotrope cell line, LbetaT2, is induced 4-fold by BMP-7 or BMP-6 treatment. BMP-7 and BMP-6 also increase endogenous FSH secretion by 10- and 14-fold, respectively, from LbetaT2 cells, demonstrating for the first time that BMP-7 and BMP-6 may be significant FSH stimulators. BMP-7 or BMP-6 can also stimulate oFSH beta Luc expression in primary pituitary cell cultures derived from transgenic mice. Neutralizing antibodies to BMP-7, which do cross-react with BMP-6 but not Activin A, decrease basal oFSH beta Luc expression and FSH secretion from the transgenic mouse pituitary cultures. Neutralizing antibodies to either Activin A or Activin B, however, do not significantly decrease basal oFSH beta Luc expression and FSH secretion. Detection of BMP-7 and BMP-6 mRNA in the transgenic mouse pituitary cells confirmed that BMP-7 and BMP-6 were being produced by these cells. Collectively, these results suggest an autocrine or paracrine role for the TGF-beta superfamily members, BMP-7 and BMP-6, in promoting FSH synthesis.