Bone Morphogenetic Protein-15 Inhibits Follicle-stimulating Hormone (FSH) Action by Suppressing FSH Receptor Expression

Abstract

We have recently reported that oocyte-derived bone morphogenetic protein-15 (BMP-15) can directly modulate follicle-stimulating hormone (FSH) action in rat granulosa cells. Here, we investigate underlying mechanisms of this BMP-15 effect. Treatment with BMP-15 alone exerted no significant effect on the basal expression of mRNAs encoding steroidogenic acute regulatory protein, P450 side chain cleavage enzyme, P450 aromatase, 3␤-hydroxysteroid dehydrogenase, luteinization hormone receptor, and inhibin/activin subunits. However, BMP-15 markedly inhibited the FSH-induced increases in these messages. In striking contrast, BMP-15 did not change the forskolin-induced levels of these transcripts. Thus, the inhibitory effect of BMP-15 on FSH action must be upstream of cAMP signaling. We next examined changes in FSH receptor mRNA expression. Interestingly, BMP-15 severely reduced the levels of FSH receptor mRNA in both basal and FSH-stimulated cells. To determine whether this effect was at the level of FSH function, we investigated the effect of BMP-15 on FSH bioactivity. Consistent with the mRNA data, BMP-15 inhibited the biological response of FSH, but not that of forskolin. Based on these results, we propose that BMP-15 is an important determinant of FSH action through its ability to inhibit FSH receptor expression. Because FSH plays an essential role in follicle growth and development, our findings could have new implications for understanding how oocyte growth factors contribute to folliculogenesis.

Aromatase expression in the ovary: Hormonal and molecular regulation

“…Factors produced by the oocytes such as BMP-15 [23] and GDF-9 [24,25] inhibit the FSH-induced increase in aromatase expression. In addition, in GDF-9 deficient mice, which manifest an arrest of preantral follicular growth, there is a premature expression of aromatase in preantral follicles [26].…”

Physiological effects of major genes affecting ovulation rate in sheep

“…In rodents, both BMP15 and GDF9 stimulate proliferation of cultured granulosa cells from antral follicles, whereas in sheep only recombinant ovine BMP15 has been shown to induce modest proliferation [25,31] (McNatty, unpublished data). An explanation for the higher ovulation rate observed in heterozygous Inverdale or Hanna ewes has been offered by Shimasaki and his colleagues [25] based on their in vitro findings that BMP15 may reduce the sensitivity of granulosa cells to FSH by inhibiting expression of the FSH receptor. Thus, in animals such as the heterozygous Inverdale or Hanna with a lower than normal concentration of BMP15, a higher FSH-induced granulosa cell responsiveness would result.…”

Effect of Intracellular Interactions on the Processing and Secretion of Bone Morphogenetic Protein-15 (BMP-15) and Growth and Differentiation Factor-9

“…Based on our previous findings on the in vitro biological effects of recombinant BMP-15, we have presented a model by which the levels of bioactive BMP-15 may account for the divergent phenotypes of the heterozygous and homozygous Inverdale ewes (12,26,27). In the heterozygotes of Inverdale ewes, the reduced level of bioactive BMP-15 results in higher levels of follicle-stimulating hormone (FSH) receptor in the granulosa cells which in turn leads to more developing healthy follicles with more luteinizing hormone (LH) receptors, resulting in precocious follicle growth and increased ovulation at earlier stages of follicular development.…”