The BMP4-Smad signaling pathway regulates hyperandrogenism development in a female mouse model
The BMP4-Smad signaling pathway regulates hyperandrogenism development in a female mouse model
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DOI：
10.1074/jbc.m117.781369
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发表时间：
2017-07-14
影响因子：
4.8
通讯作者：
Xu, Cong-Jian
中科院分区：
文献类型：
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作者：
Liu, Yang;Du, Shao-Yue;Xu, Cong-Jian
多囊卵巢综合征是一种常见的内分泌疾病，是育龄妇女无排卵性不孕的主要原因。大多数多囊卵巢综合征患者有高雄激素血症，由过量雄激素合成引起。骨形态发生蛋白4（Bone morphogenetic protein 4，BMP 4）是胚胎发育和器官形成的重要调节因子，近年来的研究表明BMP 4可能参与雌性类固醇激素的合成。然而，BMP 4对高雄激素血症的影响仍然未知。在这里，使用雌性小鼠高雄激素血症模型，我们发现卵巢BMP 4水平显着降低高雄激素血症。升高的雄激素通过激活雄激素受体抑制BMP 4表达。此外，BMP 4处理抑制卵泡膜细胞中的雄激素合成，并通过调节类固醇生成酶（包括CYP 11 A、HSD 3B 2、CYP 17 A1和CYP 19 A1）的表达促进颗粒细胞中的雌激素生成。一致地，BMP 4的敲低增加雄激素水平并抑制雌激素水平。从机制上讲，Smad信号而不是p38 MAPK通路调节雄激素和雌激素的形成，从而介导BMP 4的作用。值得注意的是，BMP 4转基因小鼠受到保护，免受高雄激素血症。我们的观察结果阐明了BMP 4在控制性激素水平方面的重要作用，并为通过靶向BMP 4-Smad信号通路干预管理高雄激素血症提供了新的见解。
Polycystic ovary syndrome is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with polycystic ovary syndrome have hyperandrogenism, caused by excess androgen synthesis. Bone morphogenetic protein 4 (BMP4) is an essential regulator of embryonic development and organ formation, and recent studies have also shown that BMP4 may be involved in female steroidogenesis process. However, the effect of BMP4 on hyperandrogenism remains unknown. Here, using a female mouse model of hyperandrogenism, we found that ovarian BMP4 levels were significantly decreased in hyperandrogenism. Elevated androgens inhibited BMP4 expression via activation of androgen receptors. Moreover, BMP4 treatment suppressed androgen synthesis in theca cells and promoted estrogen production in granulosa cells by regulating the expression of steroidogenic enzymes, including CYP11A, HSD3B2, CYP17A1, and CYP19A1. Consistently, knockdown of BMP4 augmented androgen levels and inhibited estrogen levels. Mechanistically, Smad signaling rather than the p38 MAPK pathway regulated androgen and estrogen formation, thereby mediating the effect of BMP4. Of note, BMP4-transgenic mice were protected against hyperandrogenism. Our observations clarify a vital role of BMP4 in controlling sex hormone levels and offer new insights into intervention for managing hyperandrogenism by targeting the BMP4-Smad signaling pathway.