Orexins Suggest Possible Treatment for Osteoporosis

What are orexins? They are a type of protein that nerve cells use to communicate with each other. Researchers at the University of Texas Southwestern Medical Center at Dallas, working with Yihong Wan, M.D., have found that mice lacking orexins have very thin fragile bones that break easily. They found that the bones have fewer osteoblasts. They already knew that orexins regulate behaviors such as arousal, appetite, and energy expenditure and that an orexin deficiency causes narcolepsy. The discovery raises possibilities for treatment of osteoporosis since the effect of a deficiency of orexin on bones was not previously known.

Wan, who is an assistant professor of pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study that was published in the journal Cell Metabolism, said, “Osteoporosis is highly prevalent, especially among post-menopausal women. We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis.”

Osteoporosis affects more than 10 million Americans and is responsible for more than 1.5 million fractures every year. One-in-five people who fracture a hip end up spending the rest of their lives in nursing homes.

The University press release explained the dual role played by orexins in that they both promote and block bone formation. “On the bones themselves, orexins interact with another protein, orexin receptor 1 (OX1R), which decreases the levels of the hunger hormone ghrelin. This slows down the production of new osteoblasts and, therefore, blocks bone formation locally. At the same time, orexins interact with orexin receptor 2 (OX2R) in the brain. In this case, the interaction reduces the circulating levels of leptin, a hormone known to decrease bone mass, and thereby promotes bone formation. Therefore, osteoporosis prevention and treatment may be achieved by either inhibiting OX1R or activating OX2R.”

“We were very intrigued by this yin-yang-style dual regulation, ” said Wan. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”

The work represents a profitable collaboration between researchers in the U.S. and Japan. A laboratory run by Masashi Yanagisawa, M.D., discovered orexins in 1990. Yanagisawa was an adjunct professor of molecular genetics at UT Southwestern, a Howard Hughes Medical Institute investigator, and is now with the International Institute for Integrative Sleep Medicine at the University of Tsukuba, in Japan.