Endocrine Abstracts

Here, we investigated roles of p38 MAPK pathway in the regulation of FSH-induced steroidogenesis using co-culture of rat primary granulosa cells with oocytes. The p38 protein was readily phosphorylated in granulosa cells by treatment with activin and FSH. The activin effect on p38 phosphorylation was abolished by a selective ALK-4, -5, -7 inhibitor SB431542. SB431542 suppressed FSH-induced estradiol production, but had no effect on progesterone production with a marginal reduction of cAMP synthesis, suggesting that endogenous activin is primarily involved in regulation of FSH-induced estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH-induced p38 activation occurred not through the endogenous activin actions. We also found that BMP-2 and BMP-4 enhanced FSH-induced p38 phosphorylation, which was augmented in the presence of oocytes. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. In contrast to activin effects on upregulating progesterone production, BMP-2 and BMP-4 inhibited FSH- and forskolin-induced progesterone and cAMP synthesis regardless of oocytes. BMP-2, BMP-4 and activin increased FSH-induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced forskolin-induced estradiol production, BMP-2 and BMP-4 had no effects on forskolin-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH-receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH-induced cAMP synthesis, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from cAMP-PKA pathway. Thus, BMP-2 and BMP-4 differentially regulate FSH-induced steroidogenesis by stimulating FSH-induced p38 and suppressing cAMP in granulosa cells. The former mechanism is involved in estradiol production and enhanced by oocyte actions, while the latter leads to reduction of progesterone synthesis.