A drug that can reverse diabetes and obesity in mice may have an unexpected benefit: strengthening bones. Experiments with a compound called TNP (2,4,6-trinitrophenol, which is also known as picric acid), which researchers often use to study obesity and diabetes, show that in mice the therapy can promote the formation of new bone. That’s in contrast to many diabetes drugs currently in wide use that leave patients’ bones weaker. If TNP has similar effects in humans, it may even be able to stimulate bone growth after fractures or prevent bone loss due to aging or disuse.
As more and more patients successfully manage diabetes with drugs that increase their insulin sensitivity, doctors and researchers have observed a serious problem: The drugs seem to decrease the activity of cells that produce bone, leaving patients prone to fractures and osteoporosis.
“There are millions and millions of people that have osteoporosis [with or without diabetes], and it's not something we can cure,” says Sean Morrison, a stem cell researcher at University of Texas Southwestern in Dallas. “We need new agents that promote bone formation.”
Morrison and his colleagues have shown that a high-fat diet causes mice to develop bones that contain more fat and less bone. The diet increased the levels of leptin—a hormone produced by fat cells that usually signals satiety in the brain—in the bone marrow, which promoted the development of fat cells instead of bone cells. That suggests that nutrition has a direct effect on the balance of bone and fat in the bone marrow.
After reading Morrison’s work, Siddaraju Boregowda, a stem cell researcher at the Scripps Research Institute in Jupiter, Florida, was reminded of genetically altered mice that don’t gain body fat or develop diabetes, even when fed high-fat diets. He and his boss, stem cell researcher Donald Phinney, wondered whether those mice were also protected from the fattening of the bone marrow that accompanies a high-fat diet.
They contacted Anutosh Chakraborty, a molecular biologist who was studying such mice down the hall at Scripps at the time. The animals lack the gene for an enzyme called inositol hexakisphosphate kinase 1 (IP6K1), which is known to play a role in fat accumulation and insulin sensitivity. The scientists suspected that the lost enzyme might affect the animals' mesenchymal stem cells (MSCs)—stem cells found in the bone marrow that are capable of developing into both the bone cells and fat cells that make up our skeletons. If too many fat cells develop, they take the place of bone cells, weakening the bone.
The researchers fed genetically altered and normal mice a high-fat diet for 8 weeks. Not only did the genetically altered mice develop fewer fat cells than their normal counterparts, but their production of bone cells was higher than that of the normal mice, the team reported last month in Stem Cells.
The scientists then set out to see whether they could use a drug to achieve the same effect in normal mice. For 8 weeks, they fed normal mice a high-fat diet and gave them daily injections of either TNP, a well-known IP6K1 inhibitor, or a placebo. When they analyzed the animals’ bones and marrow, they found that mice that had received TNP had significantly more bone cells, fewer fat cells, and greater overall bone area. The IP6K1 inhibitor apparently protected the mice from the detrimental effects of the high-fat diet.
The study “provided the surprising result that one new therapy currently being explored to lower insulin resistance promotes, rather than decreases, the formation of bone in mice,” says Darwin Prockop, a stem cell researcher at Texas A&M College of Medicine in Temple, who was not involved in the work.
The researchers still need to figure out how to deliver TNP’s effects only to MSCs, instead of the entire body, given that it sometimes blocks other enzymes along with IP6K1. Inhibition of IP6K1 is a promising target for patients with both diabetes and obesity, Boregowda says. He says he and his colleagues are now enthusiastic about testing their findings in a wide range of bone-related diseases and disorders. It might even help heal broken bones, he speculates.
Phinney, on the other hand, is aiming even higher. He wonders whether the therapy could also be useful for space travel, because bones are especially vulnerable to deterioration in zero gravity. “It’s a whole new field of science and drug discovery.”