Orthopaedic surgeons who treat patients with low bone mass may be particularly interested in the work of Ryan Riddle, director of the Johns Hopkins Diabetes Research Center’s Bone Biology Subcore.

Riddle and his team have discovered a link among the protein, sclerostin—which has a dramatic effect on bone mass—and whole-body metabolism. Riddle explains: “This protein was discovered recently by studying a small percentage of people who have very high bone mass. Their bone mass becomes so high that they start to develop nerve palsies because their nerve canals start to fill in [with bone] and they can’t get nerve conduction. It’s called sclerosteosis or Van Buchem disease.” Sclerostin, which is made primarily in bone, was found to dramatically increase bone mass when inhibited.

Researchers in Riddle’s lab, along with the lab of colleague Tom Clemens, are working to understand the interaction between bone and the metabolism of the whole organism. To that end, Riddle is using a knockout mouse model that lacks sclerostin.

“As we would expect from the human studies, this mouse has dramatic increases in bone volume,” says Riddle. “But we’ve also discovered something else.” When they challenge the mice with a high-fat diet, the mice don’t gain body fat as expected. “They don’t develop the phenotypes that are associated with diabetes in humans,” Riddle says. “They retain some of their insulin sensitivity.”

This indicates that the comorbid condition of low bone mass found in many patients with diabetes may be linked to sclerostin, potentially providing a common therapeutic target for both conditions. Riddle says this research may also be applicable to patients taking glucocorticoids, who are at risk for reduction in bone volume and increase in fat mass.

“Glucocorticoids are associated with changes in glucose homeostasis and insulin sensitivity,” he says. “One of the ways glucocorticoids influence bone is through regulating sclerostin, so we’re planning to explore sclerostin in that context too.”

Riddle says his work benefits from the robust research environment at Johns Hopkins. “We have the ability to interact with many people in lots of different fields,” he says. “Many of our studies are exploring effects outside the skeleton, like the physiology of adipose, the liver or the pancreas. We’ve benefited from the ability to collaborate with investigators like Michael Wolfgang in the Department of Biological Chemistry and Mehboob Hussain in the Department of Pediatrics. They are helping us move beyond the bone, which is our area of expertise.”

This emphasis on integrative physiology is a hallmark of the work of musculoskeletal researchers at Johns Hopkins. By expanding their teams to include experts in other fields and using the models their colleagues have developed for studying different organ systems, they not only strengthen their understanding of the musculoskeletal system, but also contribute more broadly to research that will underpin future therapies for a wide variety of common conditions.