BioEd Online

The traditional view of the skeleton as an inert frame is challenged by a new study showing that it also plays an important part in the body's hormonal system. Cells in the bone produce a hormone that influences blood sugar levels and fat deposition.

The study could in time lead to new approaches to the treatment of diabetes, and is being heralded by others in the field as a landmark. The findings went beyond what the researchers had expected when they first looked into the subject.

"I was surprised by the extent of the discovery," says Gerard Karsenty, lead author on the paper and an expert in skeletal development at Columbia University in New York. "It seems the skeleton acts as a rheostat, regulating metabolism." However he points to the need for further study to find out how important the effect is.

Karsenty and his colleagues had previously shown that bone metabolism was influenced by fat cells¹. Using a kind of endocrinology version of Newton's third law — that for every action there is an equal and opposite reaction — he hypothesized that if fat cells were influencing bone, bone should be influencing fat. So his team set out to find molecules in bone-producing osteoblast cells that could influence the body's metabolism.

Dual role

In this week's issue of Cell, they report that a hormone called osteocalcin released by osteoblasts does just that². Mice lacking this molecule showed glucose intolerance and insulin resistance; they had fewer beta-cells, which produce insulin, than normal mice do. Lack of beta-cells and failure to produce insulin is characteristic of Type 1 diabetes, whereas insulin resistance leads to Type 2 diabetes.

Karsenty and colleagues also suppressed the expression of a gene known as Esp which describes a receptor protein and is normally active in osteoblasts. Mice that had had the gene inactivated were protected from obesity and glucose intolerance. These were hypoglycaemic and had increased beta-cells, insulin secretion and insulin sensitivity — in some ways the opposite of diabetes, and the opposite of the effects of too little osteocalcin. Reducing the degree to which the osteocalcin gene is expressed in such mice produced a "remarkable reversal" of these effects, the researchers report.

This suggests that osteocalcin plays an extraordinary dual role. "The peculiarity that makes it potentially so important is it increases both insulin secretion and insulin sensitivity," says Karsenty.

This dual role is important because increases in insulin secretion are normally accompanied by a decrease in the sensitivity to insulin. Karsenty and others in the field say its unusual behaviour means that osteocalcin could potentially be used as a treatment for people with diabetes. But how important this endocrine regulation mechanism is in humans remains to be determined. "Nothing is certain in biology but, this said, the gene is present in mice and in humans, the protein is present in mice and humans," says Karsenty.

Importance unclear

Markus Stoffel, who researches the genetic and biochemical regulation of glucose metabolism at the Swiss Federal Institute of Technology in Zurich, agrees with the caveat. "The only big question mark is how important is that for the human?" he asks. "We know bone metabolism is somewhat different between mice and humans." But he is excited by the research and its implications: "The skeleton was always thought of as being for walking upright and as the location of the bone marrow, and that's it really," says Stoffel. "This is the first definite study that shows it's an endocrine organ."

Despite this unknown, proof that the skeleton is an endocrine organ is a "major finding", according to Graham Williams, endocrinology expert at Imperial College London, who heard some of Karsenty's findings at a conference earlier this year. "It certainly caused quite a stir," he says. "People in the field do think it's a novel idea, and likely to turn out to be a paradigm shift. Actually to identify a putative factor is certainly a major finding."