Investigation for the mechanism of reproductive endocrine regulation by bone morphogenetic proteins

正常卵泡发育受促性腺激素和卵巢生长因子控制，其中骨形态发生蛋白（BMPs）调节卵泡发生和类固醇生成。本研究旨在探讨骨形态发生蛋白对卵泡刺激素（FSH）诱导的大鼠原代颗粒细胞类固醇合成的调控机制。我们在2006年的研究发现了一种新的骨形成蛋白和MAP激酶（MAPK）信号之间的相互作用，在类固醇生成的差异调节中发挥关键的生理作用。BMP-7通过抑制卵母细胞存在下ERK磷酸化而优先增加FSH诱导的雌二醇产生。在2007年的一项研究计划中，我们研究了p38 MAPK通路在调节类固醇生成中的作用。FSH和激活素独立激活颗粒细胞中p38 MAPK磷酸化。值得注意的是，BMP-2和BMP-4增强颗粒细胞中FSH诱导的p38磷酸化，卵母细胞进一步增强了这种作用。因此，BMP-2、-4、-6和-7通过刺激FM诱导的MAPK信号传导差异地调节FSH诱导的类固醇生成。在正常卵泡发育中，卵母细胞-颗粒细胞通讯对FSH诱导的类固醇生成的差异调节至关重要。由于每种BMP都参与正常卵泡发生的关键过程，BMP将是临床诊断卵泡状况的合适标志物，也是卵巢功能障碍治疗药物的候选者。

Normal follicular development is controlled by gonadotropins as well as ovarian growth factors, in which bone morphogenetic proteins (BMPs) regulate folliculogenesis and steroidogenesis. We studied the regulatory mechanism of BMPs on follicule-stimulating hormone (FSH)-induced steroidogenesis by rat primary granulosa cells with oocytes. Our studies in 2006 uncovered a new interaction between BMPs and MAP kinase (MAPK) signaling plays key physiological roles in differential regulation of steroidogenesis. BMP-7 preferentially increased FSH-induced estradiol production through inhibiting ERK phosphorylation in the presence of oocytes. In a research plan for 2007, we investigated roles of p38 MAPK pathway in regulating steroidogenesis. FSH and activin independently activated p38 MAPK phosphorylation in granulosa cells. Notably, BMP-2 and BMP-4 enhanced FSH-induced p38 phosphorylation in granulosa cells and the effect was further augmented by oocytes. Thus, BMP-2, -4, -6 and -7 differentially regulate FSH-induced steroidogenesis by stimulating FM-induced MAPK signaling. The oocyte-granulosa cell communication is crucial for differential regulation of FSH-induced steroidogenesis in normal follicular development. Given the fact that each BMP is involved in the key process of normal folliculogenesis, BMP would be a suitable marker for clinical diagnosis of follicular conditions as well as a candidate for therapeutic agents for ovarian dysfunction.