Bone morphogenetic proteins are mediators of luteolysis in the human corpus luteum

Bone morphogenetic proteins (BMPs), members of the tumor growth factor β superfamily, play important roles in folliculogenesis in various species, however, little is known about their role in luteal function. In this study, we investigated the expression, regulation, and effects of BMP2, BMP4, and BMP6 in carefully-dated human corpora lutea and cultured human luteinized granulosa cells. The mRNA abundance of BMPs was increased in the regressing corpus luteum in vivo (P<0.01-0.001). Human chorionic gonadotropin (hCG) down-regulated BMP2, BMP4, and BMP6 transcripts both in vivo (P=0.05-0.001) and in vitro (P<0.001), and decreased the mRNA abundance of BMP receptors (BMPR1A, BMPR1B, BMPR2; P<0.05-0.01) in vitro. Three BMPs were regulated by differential signaling pathways. H89, a protein kinase A inhibitor, increased the expression of both BMP2 (P<0.05) and BMP4 (P<0.05) while decreasing BMP6 (P<0.01). PMA, a protein kinase C activator, decreased both BMP4 and BMP6 expression (P<0.0001) while enhancing the mRNA abundance of BMP2 (P<0.01). BMPs significantly down-regulated transcripts for LH/choriogonadotropin receptor (LHCGR; P<0.001) and steroidogenic acute regulatory protein (STAR; P<0.001), while up-regulating those of follicular stimulating hormone receptor (FSHR; P<0.01) and aromatase (CYP19A1; P<0.05-0.01) in vitro, possessing an effect opposite to hCG but similar to Activin A. Like Activin A, BMP4 and BMP6 stimulated the expression of Inhibin/Activin subunits with a marked effect on INHBB expression (P<0.05-0.01). These data confirm that BMPs are increased during luteal regression and negatively regulated by hCG via differential mechanisms, suggesting that BMPs are one of the mediators of luteolysis in women.