TGF-β Superfamily Regulation of Follicle-Stimulating Hormone Synthesis by Gonadotrope Cells: Is There a Role for Bone Morphogenetic Proteins?

Abstract

Bone morphogenetic proteins (BMPs) are pleiotropic ligands in the TGF-β superfamily. In the early to mid-2000s, several BMPs, including BMP2, were shown to regulate FSH synthesis alone and in synergy with activins in immortalized gonadotrope-like cell lines and primary pituitary cultures. Activins are also TGF-β family members, which were identified and named based on their abilities to stimulate FSH production selectively. Mechanistic analyses suggested that BMP2 promoted expression of the FSHβ subunit gene (Fshb) via at least two nonmutually exclusive mechanisms. First, BMP2 stimulated the production of the inhibitor of DNA-binding proteins 1, 2, and 3 (Id1, Id2, and Id3), which potentiated the stimulatory actions of homolog of Drosophila mothers against decapentaplegic 3 (SMAD3) on the Fshb promoter. SMAD3 is an intracellular signaling protein that canonically mediates the actions of activins and is an essential regulator of Fshb production in vitro and in vivo. Second, BMP2 was shown to activate SMAD3-dependent signaling via its canonical type IA receptor, BMPR1A (also known as ALK3). This was a surprising result, as ALK3 conventionally activates distinct SMAD proteins. Although these initial results were compelling, they were challenged by contemporaneous and subsequent observations. For example, inhibitors of BMP signaling did not specifically impair FSH production in cultured pituitary cells. Of perhaps greater significance, mice lacking ALK3 in gonadotrope cells produced FSH normally. Therefore, the physiological role of BMPs in FSH synthesis in vivo is presently uncertain.

Figure 1.

Proposed models of activin and BMP regulation of FSHβ subunit (Fshb) and inhibitor of DNA-binding protein (Id)1/2/3 transcription. Activin and BMP signaling are depicted on the left and right, respectively. ACVR2A, activin receptor type II A; ACVR2B, activin receptor type IIB; ALK, activin receptor-like kinase, type I receptor; BMPR2, BMP receptor type II; FOXL2, forkhead box L2; LDN193189, small molecule ALK2/3/6 inhibitor; SMAD, homolog of Drosophila mothers against decapentaplegic.

Figure 2.

Noggin does not regulate Fshb expression in murine pituitary cultures. Pituitary cells were isolated from male wild-type C57BL/6 mice and treated in culture with noggin (30 or 300 ng/mL) or SB431542 (384 ng/mL, 1 µM) for 24 hours. Fshb mRNA expression was determined by quantitative RT-PCR. Data represent the means (+SEM) of three to four independent experiments. ****P < 0.0001, one-way ANOVA, followed by Sidak multiple comparisons.