Bone morphogenetic protein-15 inhibits follicle-stimulating hormone (FSH) action by suppressing FSH receptor expression

We have recently reported that oocyte-derived bone morphogenetic protein-15 (BMP-15) can directly modulate follicle-stimulating hormone (FSH) action i n rat granulosa cells. Here, we investigate underlying mechanisms of this B MP-15 effect. Treatment with BMP-15 alone exerted no significant effect on the basal expression of mRNAs encoding steroidogenic acute regulatory prote in, P450 side chain cleavage enzyme, P450 aromatase, 3 beta -hydroxysteroid dehydrogenase, luteinization hormone receptor, and inhibin/activin subunit s. However, BMP-15 markedly inhibited the FSH-induced increases in these me ssages. In striking contrast, BMP-15 did not change the forskolin-induced l evels of these transcripts, Thus, the inhibitory effect of BMP-15 on FSH ac tion must be upstream of cAMP signaling. We next examined changes in FSH re ceptor mRNA expression. Interestingly, BMP-15 severely reduced the levels o f FSH receptor mRNA in both basal and FSH-stimulated cells. To determine wh ether this effect was at the level of FSH function, we investigated the eff ect of BMP-15 on FSH bioactivity, Consistent with the mRNA data, BMP-15 inh ibited 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 ac tion through its ability to inhibit FSH receptor expression. Because FSH pl ays an essential role in follicle growth and development, our findings coul d have new implications for understanding how oocyte growth factors contrib ute to folliculogenesis.