Our bones have much greater influence on the rest of our bodies than they are often given credit for, according to two new studies in the July 23 issue of Cell, a Cell Press publication. Both studies offer new insights into the interplay between bone and blood sugar, based on signals sent via insulin and a bone-derived hormone known as osteocalcin.

Mice whose bones can't respond to insulin develop high blood sugar and insulin resistance, both hallmarks of diabetes. Those symptoms are tied to a drop in osteocalcin. The findings suggest that osteocalcin, or perhaps a drug that targets bone, might hold promise in fighting the global epidemic of type 2 diabetes, according to the researchers.

"Our study reveals a key molecular link between bone remodeling and metabolism," said Gerard Karsenty of Columbia University.

"Bone is an organ that has to pay attention to where calories are going," added Thomas Clemens of Johns Hopkins University School of Medicine. "It talks to muscle, fat, the pancreas. It's a player in energy metabolism."

And perhaps that makes a lot of sense, Karsenty said. The remodeling of bone relies on two cell types, bone-building osteoblasts and bone-resorbing osteoclasts, making bone the only organ with a cell type that is entirely focused on destroying host tissue. "On a daily basis, the formation of bone is expensive in terms of energy," he said.

In fact, the idea that the skeleton is much more than a reservoir for calcium and phosphate isn't entirely new, the researchers said. Earlier evidence by Karsenty's group had shown links between bone and the fat hormone leptin. (Obese adults are significantly less likely to develop osteoporosis.)

Scientists also had evidence that osteoblasts might respond to insulin in important ways. Osteoblasts bear insulin receptors and when treated with insulin show signs of collagen synthesis and take up more glucose, Clemens' team notes. People with type 1 diabetes due to a lack of insulin can also develop weakened bones.

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Karsenty's team describes bone as a multitasker. It has mechanical, hematopoietic (blood-producing) and metabolic functions. It also acts as an endocrine organ through the release of osteocalcin hormone, which favors glucose metabolism when in its active form.

Still, Clemens said he was surprised by what they saw after developing a mouse lacking insulin receptors only in their osteoblasts. "The mice started to get fat," he said. They showed changes in their biochemistry that were consistent with insulin resistance. They also had low osteocalcin levels and fewer osteoblasts to produce less bone.

With age, the animals became even fatter and developed more marked high blood sugar accompanied by severe glucose intolerance and insulin resistance. Those symptoms improved with osteocalcin treatment.

Karsenty's group presents independent evidence for the important role of insulin in bone for keeping glucose in check through osteocalcin, in what he refers to as a "feed-forward loop." But his group goes a step further to suggest that bone-resorbing osteoclasts (not just osteoblasts) have a place in this too.

Karsenty explains that bone-building osteoblasts actually control bone resorption by osteoclasts, a process that takes place under very acidic conditions. Those conditions would also favor the chemical modification necessary to produce active osteocalcin, which can escape bone to act as a hormone.

That could be important to those who take osteoporosis drugs designed to block bone resorption, Karsenty suggests. "It's a red flag," he said. "Osteoporotic patients treated with [bone resorption inhibitors] may be at risk of glucose intolerance."

The researchers include Mathieu Ferron, Columbia University, New York, NY; Jianwen Wei, Columbia University, New York, NY; Tatsuya Yoshizawa, Columbia University, New York, NY; Andrea Del Fattore, University of L'Aquila, L'Aquila, Italy; Ronald A. DePinho, Harvard Medical School, Boston, MA; Anna Teti, University of L'Aquila, L'Aquila, Italy; Patricia Ducy, Columbia University, New York, NY; and Gerard Karsenty, Columbia University, New York, NY.