Department of General Medicine and Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Biochem Biophys Res Commun. 2021 Jun 25;559:56-61. doi: 10.1016/j.bbrc.2021.04.085. Epub 2021 Apr 28.
To elucidate the impact of glucocorticoids on ovarian steroidogenesis and its molecular mechanism by focusing on bone morphogenetic proteins (BMPs), we examined the effect of dexamethasone (Dex) on estradiol and progesterone synthesis by using primary culture of rat granulosa cells. It was revealed that Dex treatment dose-dependently decreased estradiol production but increased progesterone production induced by follicle-stimulating hormone (FSH) by granulosa cells. In accordance with the effects of Dex on estradiol synthesis, Dex suppressed P450arom mRNA expression and cAMP synthesis induced by FSH. Dex treatment in turn enhanced basal as well as FSH-induced levels of mRNAs encoding the enzymes for progesterone synthesis including P450scc and 3βHSD but not StAR and 20αHSD. Of note, Dex treatment significantly upregulated transcription of the BMP target gene Id-1 and Smad1/5/9 phosphorylation in the presence of BMP-15 among the key ovarian BMP ligands. It was also found that Dex treatment increased the expression level of BMP type-I receptor ALK-6 among the type-I and -II receptors for BMP-15. Inhibitory Smad6/7 expression was not affected by Dex treatment. On the other hand, BMP-15 treatment upregulated glucocorticoid receptor (GR) expression in granulosa cells. Collectively, it was revealed that glucocorticoids elicit differential effects on ovarian steroidogenesis, in which GR and BMP-15 actions are mutually enhanced in granulosa cells.
为了阐明重点关注骨形态发生蛋白（BMPs）时糖皮质激素对卵巢甾体生成的影响及其分子机制，我们使用大鼠颗粒细胞的原代培养物研究了地塞米松（Dex）对雌二醇和孕酮合成的影响。结果表明，Dex 处理以剂量依赖的方式降低了雌二醇的产生，但增加了由卵泡刺激素（FSH）诱导的孕酮的产生。与 Dex 对雌二醇合成的影响一致，Dex 抑制了 FSH 诱导的 P450arom mRNA 表达和 cAMP 合成。反过来，Dex 处理增强了编码孕酮合成酶的 mRNA 的基础水平和 FSH 诱导水平，包括 P450scc 和 3βHSD，但不包括 StAR 和 20αHSD。值得注意的是，在存在 BMP-15 的情况下，Dex 处理显著上调了 BMP 靶基因 Id-1 的转录和 Smad1/5/9 的磷酸化。还发现，在 BMP-15 的 I 型和 II 型受体中，Dex 处理增加了 BMP 型 I 受体 ALK-6 的表达水平。抑制性 Smad6/7 表达不受 Dex 处理的影响。另一方面，BMP-15 处理上调了颗粒细胞中的糖皮质激素受体（GR）表达。总之，结果表明糖皮质激素对卵巢甾体生成产生了不同的影响，其中 GR 和 BMP-15 的作用在颗粒细胞中相互增强。
