Published online 17 February 2011 | Nature | doi:10.1038/news.2011.107
Corrected online: 21 February 2011


Of femurs and fertility

Mouse studies suggest bone hormone affects male fertility.

osteoblastOsteoblasts produce a hormone that can affect fertility in male mice.PAUL GUNNING / SCIENCE PHOTO LIBRARY

A hormone produced by bone-building cells may have a role in regulating male fertility.

Osteocalcin seems to promote production of the sex steroid hormone testosterone, and increase fertility, in male mice, according to a study led by Gerard Karsenty, a geneticist at Columbia University in New York, and published in Cell1.

Decreases in sex steroid hormones can lead to loss of bone mass in humans. Karsenty and his colleagues hypothesize that, conversely, a decrease of hormones derived from bone might prompt a decline in sex hormones and fertility. They also speculated that this would be more pronounced in females. "We were betting at the beginning that it would regulate female fertility more than male fertility," Karsenty says.

In a series of experiments on mice engineered to have low levels of osteocalcin, however, the researchers consistently found that the male mice had lowered fertility, whereas osteocalcin levels had no impact on the fertility of female mice. "We were slightly wrong," Karsenty admits.

For more than a decade, Karsenty and his colleagues have been examining the idea of the skeleton as an 'endocrine organ' — and specifically one that influences energy metabolism by influencing insulin production. Yet despite a growing body of research supporting this idea, the theory that osteocalcin may affect energy metabolism remains up for debate, primarily because it is difficult to test in humans.

Translation of the new findings to humans may be relatively more straightforward. This is because the receptor, GPRC6A, that the researchers identified, through which osteocalcin affects testosterone production, is also present in men's gonads, but not women's ovaries.

"I think it might be easier to find links here," says Mark Cooper, an endocrinologist who studies osteoporosis at the University of Birmingham, UK. Cooper says the findings also contribute to a better understanding of the multifaceted role of the skeleton. "It does make the world a more bone-centric place."

Of male mice and men

Karsenty's team first determined that components of osteoblasts or bone-building cells seemed to influence the production of testosterone but not other sex hormones. In mouse-cell cultures, they also found that hormones secreted by osteoblasts influenced testosterone by acting on Leydig cells — which synthesize testosterone in the testes — suggesting that osteocalcin plays a part in boosting testosterone production. Then, in a series of experiments with live mice, they noted that males engineered to have lower levels of osteocalcin had lower levels of testosterone, and were also less fertile — producing fewer offspring per litter than male mice with normal osteocalcin levels.

To rule out the possibility that osteocalcin generated in the testes — and not derived from bone — was responsible for the enhanced fertility the researchers performed several gene-expression tests and cell-specific knockout tests. These confirmed that osteocalcin produced by bone cells influences male fertility.


They then used the fact that osteocalcin affected fertility of males but not females to home in on the receptor through which osteocalcin boosts testosterone production. They looked at which G protein-coupled receptors were expressed at high levels in the testes but not the ovaries, and then narrowed those down to the one that, when erased, caused similar infertility characteristics to those of mice that had been engineered to lack osteocalcin.

On the basis of the group's earlier research into how osteocalcin may regulate insulin — and with it, a predisposition to conditions like diabetes — Karsenty suggests that these latest findings point to osteocalcin as a versatile and vital hormone. "What this implies, in fact, is that osteocalcin has many features of a fitness hormone," Karsenty says. "I don't think it is an anti-ageing hormone," he adds. "It doesn't make mice live longer, but it makes them live better."

Cooper says the findings might prompt new analyses of long-used drugs that affect the skeleton and may have an impact on osteocalcin levels. "I think people will be rushing to find out whether these old drugs are having unexpected effects on testosterone or even fertility," he says. 


Due to an error introduced during editing, two paragraphs in an earlier version of this story implied that osteocalcin reduced rather than enhanced fertility in male mice. The article has now been corrected.
  • References

    1. Oury, F. et al. Cell doi:10.1016/j.cell.2011.02.004 (2011).
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