October 2012

The bare bones

In the 1990s, the Karsenty laboratory made a knockout mouse missing osteocalcin. The mouse was expected to have a bone phenotype, but, unexpectedly, it was a plump animal with only minor skeletal abnormalities. Around 2008, the Clemens group created a different mouse that lacked the insulin receptor on its osteoblasts. That mouse also became fat and looked just like the osteocalcin-null mouse that the Karsenty group had made a decade before. Like the Clemens group, the Karsenty group had made the mouse missing the insulin receptor in osteoblasts and had gotten the same phenotype. The mouse studies “linked insulin signaling in the osteoblasts to the production of osteocalcin,” says Clemens.

The thinking now goes that insulin stimulates osteocalcin production by osteoblasts. The osteocalcin molecule gets stored in the mineralized matrix. When osteoclasts dissolve bone, osteocalcin enters the bloodstream. From there, researchers have shown, one of the post-translationally modified forms of osteocalcin increases insulin secretion from the pancreas and enhances the ability of adipocytes to use glucose.

Sclerostin-inhibited bone formation 
Sclerostin inhibits osteoblast-mediated bone formation. Image credit: Amgen 

Because bone remodeling demands a lot of energy, “this new paradigm really allows us to think about the skeleton as the sensor for metabolic activity and also as a fine-tuner for insulin sensitivity,” says Clifford Rosen at the Maine Medical Center Research Institute. “It takes a lot of energy to make bone. We don’t know anything about the dynamics of how these cells use their energy.”

The knockout mice have been critical in revealing osteocalcin’s purpose, but there is a question mark hanging over the extent to which osteocalcin influences the insulin pathway in humans, say Clemens and Rosen. “The mouse has given us tremendous insights, but moving to humans, it’s much more complicated,” says Rosen. “We need to get a better idea of how important is osteocalcin in fine-tuning insulin secretion.”

Clemens and Rosen explain that in some mouse models osteocalcin looks to be critical for regulating the insulin pathway. But mice aren’t metabolic equivalents of us, because their metabolic rates are 100 to 1,000 times faster than ours. Both Rosen and Clemens say the differences in metabolic rates raise the question of whether the osteocalcin effects seen in mice come about simply because of the peculiarities of mouse metabolism. “It’s a big challenge,” says Rosen. “How do we apply what we see in mice to humans?”

And that is exactly what the next research steps should answer, says Clemens. He says that, while association studies in humans seem to suggest osteocalcin has an effect on insulin secretion, there haven’t been any studies that show a clear cause-and-effect relationship. Those kinds of studies are begging to be done.

Osteoporosis drugs
Understanding fundamental bone biology has had great repercussions for one of the most recognized diseases of bone: osteoporosis. Osteoporosis appears in postmenopausal women, the elderly and people suffering from some diseases, such as anemia. The bones become fragile and easily snap. According to the National Osteoporosis Foundation, about 34 million Americans are at risk for the disease. By 2025, the foundation projects, osteoporosis will cost the American healthcare system $25.3 billion per year.

Osteoporosis happens when osteoclasts outstrip osteoblasts in performance. The reason postmenopausal women are more at risk is thought to be that estrogen indirectly inhibits the activity of osteoclasts. But after menopause, estrogen’s protection disappears, and the osteoclasts start breaking down bone more quickly than osteoblasts can keep up. The speeding up of osteoclasts starts happening in the elderly for reasons yet to be deciphered. This causes elderly people to grow hunched, shrink in height and become more susceptible to broken bones.

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  • I enjoy reading your articles. They are all superbly written. Bishnu

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