Endocrine Regulation of Male Fertility by the Skeleton

Bone is a dynamic tissue undergoing modeling during childhood and remodeling throughout adulthood. These processes are characterized by the succession of resorption of mineralized bone by osteoclasts and de novo formation by osteoblasts. One of the most powerful hormonal regulations of bone remodeling is exerted by the sex steroid hormones that are necessary to maintain bone integrity. The biological importance of this regulation is best exemplified by the fact that gonadal failure triggers bone loss and causes osteoporosis in postmenopausal women. The study of the interplay between gonads and bone has historically focused on the mechanism whereby sex steroid hormones affect bone mass accrual.
During the past 10 years, bone has emerged as an endocrine tissue. Indeed, an osteoblast-specific secreted molecule, osteocalcin, acts, when uncarboxylated as a hormone favoring β cell proliferation, insulin secretion, and sensitivity. This action is restricted to the uncarboxylated form of osteocalcin that is released in the systemic circulation. Whether or not bone may also regulate gonadal activity has not been explored.

In a recent study, Oury and colleagues [1] explored this question and got unexpected results. Using coculture experiments, they showed that osteoblasts conditioned medium enhanced testosterone secretion by Leidig cells but had no impact on ovarian secretion. They further demonstrated that uncarboxylated osteocalcin, the major hormone secreted by osteoblasts, accounted for this effect. Conversely, male mice invalidated for osteocalcin had reduced testis size, testosterone secretion, and fertility. Inversely, mice harboring an increased osteocalcin secretion displayed an opposite phenotype. The responsibility of osteoblasts-derived osteocalcin was further confirmed through cell specific invalidation of osteocalcin gene. Using a compound approach to identify the osteocalcin receptor in Leidig cells, they first studied in vitro osteocalcin signaling and demonstrated that osteocalcin increased intracellular cAMP. Then, they seeked for an orphan G protein-coupled receptor specifically enriched in Leidig cells. This approach allowed the identification of Gprc6a as the receptor of osteocalcin in Leidig cells. Furthermore, the authors identified CREB as the major transcription factor mediating osteocalcin signaling downstream Gprc6a. In response to osteocalcin, this transcription factor upregulates the expression of several enzymes crucial for testosterone synthesis.

This study provides the first evidence that the skeleton is an endocrine regulator of male fertility. It also demonstrates a key role of osteocalcin in this process. Finally, this work identified Gprc6a as the first osteocalcin receptor.

1. Oury F. et al. Cell. 2011;144:796-809.