The Bone Connector

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Researchers uncover a genetic link between bone remodelling and energy metabolism.
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Glucose intolerance increases the risk of diabetes, heart disease and death; however, the condition may be managed with diet and exercise.

It may seem like your bones are stable and unchanging, but it may surprise you to learn that they are constantly being remodelled. Cells called osteoclasts and osteoblasts respectively erode and rebuild bone in a continuous manner—renewing one tenth of the adult skeleton each year.

Because bones provide the support structure for the entire body, the disruption of bone development and growth can lead to serious consequences. For example, those with cleidocranial dysplasia are born with genetic mutations that lead to bone malformations, including short stature, underdeveloped collarbones and holes in the skull. The genetic causes are not known in up to 40 per cent of people with this disease, but a new study by PM Senior Scientist Dr. Robert Rottapel identifies a novel genetic candidate.

Using an experimental model, Dr. Rottapel and his research team found that deletion of a gene known as Rnf146 in osteoblasts leads to short stature and malformation of the collarbones and skull—all features of cleidocranial dysplasia. The researchers dug deeper and found that loss of Rnf146 turned off a bone development pathway that involves the proteins Wnt and beta-catenin.

They also found that loss of Rnf146 turned off the production of the hormone osteocalcin, which normally promotes the release of insulin and signals the body to use sugar (glucose) for energy. The absence of osteocalcin in turn resulted in glucose intolerance, a pre-diabetic state that is characterized by an inability to use glucose as an energy source and a buildup of glucose in the blood.

"Our study has revealed a previously unknown molecular switch that controls bone development and metabolism," explains Dr. Rottapel. "Furthermore, our findings suggest that people with cleidocranial dysplasia may be at risk of developing metabolic diseases such as diabetes. Future studies are required to explore this link and potential therapeutics."

This work was supported by the Canadian Institutes of Health Research, the Ontario Institute for Cancer Research, the Japan Society for the Promotion of Science, the Japan Rheumatism Foundation, the Sumitomo Life Social Welfare Services Foundation, the Nakayama Science Foundation and The Princess Margaret Cancer Foundation.

Matsumoto Y, La Rose J, Lim M, Adissu HA, Law N, Mao X, Cong F, Mera P, Karsenty G, Goltzman D, Changoor A, Zhang L, Stajkowski M, Grynpas MD, Bergmann C, Rottapel R. Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism. J Clin Invest. 2017 Jun 30. doi: 10.1172/JCI92233.