Editors' ChoiceReproduction

Bones Break the News on Reproduction

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Science Translational Medicine  09 Mar 2011:
Vol. 3, Issue 73, pp. 73ec30
DOI: 10.1126/scitranslmed.3002339

Our bones are constantly being remodeled throughout life because of the opposing actions of osteoblast cells that build up bone and osteoclast cells that break it down. A well-known cause of bone loss and osteoporosis in women is decreased production of estrogen or failure of the ovaries that produce this sex hormone. Although it is clear that estrogen (and also testosterone) have marked effects on bone, whether bone affects the gonads has not been studied. Enter Oury et al. with their surprising discovery that a factor produced by bone, osteocalcin, induces synthesis of testosterone in the testis, thus identifying bone as an unexpected regulator of reproduction.

In their tour-de-force mouse genetics study, the authors demonstrate that osteocalcin produced by bone osteoblasts instructs Leydig cells in the testis to produce the male sex hormone testosterone, which promotes survival of male germ cells and production of sperm. Tissue-specific inactivation of osteocalcin in bone led to decreases in testosterone production, testes weight, and sperm counts, resulting in reduced male fertility without an effect on female fertility. The investigators mapped these effects to a reduction in testosterone production that caused an increase in germ cell apoptosis, resulting in decreased numbers of spermatocytes and spermatids (the progenitors of mature sperm) in osteocalcin-deficient male mice. On the basis of increased adenosine 3´,5´-monophosphate (cAMP) production in osteocalcin-stimulated Leydig cells, the authors hypothesized that the osteocalcin might mediate its effects through a G protein–coupled receptor. They identified a testis-specific orphan G protein–coupled receptor, Gprc6a, as the receptor for osteocalcin. In a key experiment, loss of Gprc6a produced the same phenotype as loss of osteocalcin and abolished binding of osteocalcin to Leydig cells. These results establish osteocalcin and Gprc6a as a ligand-receptor pair that together regulate testosterone production by Leydig cells in the testis.

The exciting study of Oury and colleagues uncovers an unexpected role for bone in the endocrine regulation of reproduction. A few years ago, this group established a link between osteocalcin produced by bone and both insulin secretion and energy metabolism, suggesting that osteocalcin may play a role in diabetes and metabolic syndrome. Here, they show that in mice osteocalcin is also important for testosterone production and testis function. Further studies are needed to confirm whether osteocalcin and its Gprc6a receptor play a role in human reproduction and whether manipulating this ligand-receptor pair could help to treat some forms of male infertility.

F. Oury et al., Endocrine regulation of male fertility by the skeleton. Cell 144, 796–809 (2011). [Abstract]

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