The BMP4-Smad Signaling Pathway Regulates Hyperandrogenism Development in a Female Mouse Model

Yang Liu; Shao-Yue Du; Meng Ding; Xin Dou; Fei-Fei Zhang; Zhi-Yong Wu; Shu-Wen Qian; Wei Zhang; Qi-Qun Tang; Cong-Jian Xu

doi:10.1074/jbc.M117.781369

The BMP4-Smad Signaling Pathway Regulates Hyperandrogenism Development in a Female Mouse Model

¹ Obstetrics and Gynecology Hospital, Fudan University; and Fudan University Shanghai Medical College, China;
² Obstetrics and Gynecology Hospital, Fudan University, China;
³ Fudan University Shanghai Medical College, China;
⁴ Fudan University Shanghai Medical School, China

↵* Corresponding author; email: qqtang{at}shmu.edu.cn

Author contributions: Y.L. and S.Y.D. designed and conducted the experiments, analyzed data, and wrote the manuscript. M.D., X.D., F.F.Z. and Z.Y.W. participated in carrying out the experiments in vivo. S.W.Q. participated in generation of recombinant adenovirus. M.D, Z.Y.W., S.W.Q. and W.Z. reviewed the manuscript and offered critical advice. Q.Q.T. and C.J.X directed the project and reviewed the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age. Most patients with PCOS 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, 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 level and inhibited estrogen level. 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.