Abstract
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.
Highlights
Polycystic ovary syndrome is a common endocrine disorder and a major cause of anovulatory sterility in women at reproductive age
The ovarian theca cells (TCs) are stimulated by luteinizing hormone (LH) or insulin, which in turn activates a series of steroidogenic enzymes, including cytochrome P450scc, ⌬5-isomerase-3-hydroxysteroid dehydrogenase type 2 (3HSD2, encoded by HSD3B2), and P450c17, thereby catalyzing the synthesis of androgens including testosterone and dihydrotestosterone [6, 7]
In addition to Bone morphogenetic protein 4 (BMP4), we found that part of the BMP family members was down-regulated in hyperandrogenism ovaries, including BMP5, BMP6, BMP8b, BMP11, BMP12, and BMP15, suggesting that BMP signaling might be impaired in hyperandrogenism
Summary
BMP4 expression in ovary was negatively related with the occurrence of hyperandrogenism. Knockdown of BMP4 augmented CYP11A, HSD3B2, and CYP17A1 expression in TCs but repressed CYP19A1 expression in GCs (Fig. 4B) Taken together, these data suggested that BMP4 inhibited androgens synthesis in ovarian TCs and promoted estrogens production in GCs. BMP4 binds to two distinct type I and type II serine/threonine kinase receptors, which activates Smad and p38 MAPK signaling pathway, thereby regulating cellular processes [12, 14]. A deficiency of Smad promoted CYP11A, HSD3B2, and CYP17A1 expression in TCs and inhibited CYP19A1 in GCs, whereas disruption of p38 MAPK could hardly affect these (Fig. 6, B and C) These results suggested that the Smad pathway, instead of p38 MAPK, mediated BMP4 function in regulating androgens and estrogens synthesis. These results together suggested that BMP4 inhibited hyperandrogenism development, which validated the results in vitro
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