Ovarian bone morphogenetic proteins in female reproduction

Although bone morphogenetic proteins (BMPs) have been well-known regulators in ectopic formation of bone and cartilage, as well as in early embryonic development, nothing was known about the role of the BMP system in regulating ovarian function until recently. We demonstrated for the first time that the BMP system exists in the mammalian ovary and plays key roles in regulating important granulosa cell (GC) functions. Specifically, all BMPs we examined, including BMP-4, -6, -7, and -15, inhibit follicle-stimulating hormone (FSH)-dependent progesterone synthesis by primary cultures of rat granulosa cells. Thus, our observations provided experimental support for the hypothesis that BMPs may be a physiologically relevant luteinization inhibitor in growing ovarian follicles. BMP-7 and -15, but not BMP-6, are mitogens for granulosa cells. BMP-6 and BMP-15 are potent inhibitors of FSH action, by suppressing adenylate cyclase activity and FSH receptor expression, respectively. BMP-15 stimulates kit ligand (KL) expression, whereas kit ligand inhibits BMP-15 expression, thus forming a novel oocyte-somatic cell negative feedback loop. The physiological importance of the BMP system for normal mammalian reproduction has been established by the elucidation of the aberrant reproductive phenotypes of animals having mutated genes encoding BMP family members. Here we provide the recent advances in our understanding of the functions of BMPs in the ovary.