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。本研究探讨了BMPs对卵泡刺激素(FSH)诱导的大鼠卵母细胞原代颗粒细胞类固醇合成的调节机制。我们在2006年的研究揭示了BMPs和MAPK之间的一种新的相互作用，MAPK信号在类固醇合成的差异调控中发挥着关键的生理作用。在有卵母细胞存在的情况下，BMP-7通过抑制ERK的磷酸化，优先增加FSH诱导的雌二醇的产生。在2007年的一项研究计划中，我们研究了p38MAPK通路在调节类固醇合成中的作用。FSH和激活素独立激活颗粒细胞中p38MAPK的磷酸化。值得注意的是，BMP-2和BMP-4增强了FSH诱导的颗粒细胞中p38的磷酸化，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信号通路不同地调节FSH诱导的类固醇合成。卵母细胞-颗粒细胞通讯对于FSH诱导的类固醇合成在正常卵泡发育中的差异调节至关重要。鉴于每个BMP都参与了正常卵泡发生的关键过程，BMP可能是临床诊断卵泡状况的一个合适的标记物，也是治疗卵巢功能障碍的候选药物。

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.