New York, NY, USA. The hormone osteocalcin is released by bone in the skeleton to regulate fertility in male mice, a model organism with high predictive value for human studies.

Osteocalcin is is a skeletal (or bone-building) protein found in bone and dentin (the calcified tissue that in our teeth) in both females and males. The hormone has received considerable past attention mainly for its possible role in bone fractures and insulin resistance. However, the new research reported on here proposes that osteocalcin may enhance testosterone synthesis and thus play a role in the regulation of male fertility.

Until now, interactions between bone and the reproductive system have focused only on the influence of gonads on the build-up of bone mass. Since communication between two organs in the body is rarely one-way, the fact that the gonads regulate bone raised the interrelated question: does bone regulate the gonads? And, if so, why does it affect male but not female reproduction?

Gerard Karsenty, M.D., Ph.D., and chair of the Department of Genetics and Development at Columbia University Medical Center (CUMC), posed the question. Karsenty and his team found their first clue to an answer in the reproductive success of their lab mice. Previously, the researchers had observed that males whose skeletons did not secrete the hormone osteocalcin were poor breeders. The new findings appear in the journal Cell.

The investigators then did several experiments that show that osteocalcin enhances the production of testosterone, a sex steroid hormone controlling male fertility. As they added osteocalcin to cells that, when in our body produce testosterone, its synthesis increased. Similarly, when they injected osteocalcin into male mice, circulating levels of testosterone also went up.

Conversely, when osteocalcin is not present, testosterone levels drop, which causes a decline in sperm count, the researchers found. When osteocalcin-deficient male mice were bred with normal female mice, the pairs only produced half the number of litters as did pairs with normal males, along with a decrease in the number of pups per litter.

If osteocalcin also promotes testosterone production in men, low osteocalcin levels may be the reason why some infertile men have unexplained low levels of testosterone. Though the findings have not yet been confirmed in humans, Dr. Karsenty expects to find similar characteristics in humans, based on other similarities between mouse and human hormones.

Skeleton Regulates Male Fertility, But Not Female

Sex hormones — estrogen in women and testosterone in men — have been known to affect skeletal growth, but until now, studies of the interaction between bone and the reproductive system have focused only on how sex hormones affect the skeleton.

Estrogen is considered one of the most powerful hormones that control bone; when ovaries stop producing estrogen in women after menopause, bone mass rapidly declines and can lead to osteoporosis. It is also known than when treatment for M2F transsexuals completely eliminates testosterone production that bone mass and density declines to a stable end point. A sufficient estrogen regimen establishes equilibrium and confers a number of other benefits to the patient.

Remarkably, although the new findings stemmed from an observation about estrogen and bone mass, the researchers could not find any evidence that the skeleton influences female reproduction. "We do not know why the skeleton regulates male fertility, and not female. said Dr. Karsenty.

Looking at the question in an evolutionary context, Karsenty says that "... if you want to propagate the species, it's probably easier to do this by facilitating the reproductive ability of males. This is the only rationale I can think of to explain why osteocalcin regulates reproduction in male and not in female mice."

Other Novel Osteocalcin Functions

The unexpected connection between the skeleton and male fertility is one of a string of surprising findings in the past few years regarding the skeleton. In previous papers, Dr. Karsenty has found that osteocalcin helps control insulin secretion, glucose metabolism and body weight.

"What this work shows is that we know so little physiology, that by asking apparently naïve questions, we can make important discoveries," Dr. Karsenty says. "It also shows that bone exerts an important array of functions all affected during the aging process."

As such, these findings suggest that bone is not just a victim of the aging process, but that it may be an active determinant of aging as well.

Next Steps for Research

"This study expands the physiological repertoire of osteocalcin, and provides the first evidence that the skeleton is a regulator of reproduction," said Dr. Karsenty. Next, the researchers plan to determine the signaling pathways used by osteocalcin to enhance testosterone production.

The current research highlighted the effects of osteocalcin on testosterone production and sperm count. However, questions of quality remain. Given recent inquiries by fertility specialists into the effects of egg and/or sperm quality, future studies will have to account for osteocalcin. Such research has already yielded discoveries that pertain to miscarriage, genetic conditions, birth anomlies, and other conditions.

And as for potential drug development, since the researchers have also identified a receptor of osteocalcin, more flexibility in designing a drug that mimics the effect of osteocalcin is expected. Whether it's for glucose metabolism or fertility, says Dr. Karsenty, knowing the receptor will make it easier for chemists to develop a compound that will bind to it.

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