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Proteins causing daytime sleepiness may be tied to bone formation, osteoporosis

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Proteins causing daytime sleepiness are tied to bone formation, a target for osteoporosis, says new research, "Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action," published online June 3, 2014 in the journal Cell Metabolism.

Orexin neuropeptides promote arousal, appetite, reward, and energy expenditure, and orexin proteins, which are blamed for spontaneous daytime sleepiness, also play a crucial role in bone formation, according to findings by UT Southwestern Medical Center researchers. The findings could potentially give rise to new treatments for osteoporosis, the researchers say.

Orexins are a type of protein used by nerve cells to communicate with each other. Since their discovery at UT Southwestern more than 15 years ago, they have been found to regulate a number of behaviors, including arousal, appetite, reward, energy expenditure, and wakefulness. Orexin deficiency, for example, causes narcolepsy – spontaneous daytime sleepiness. Thus, orexin antagonists are promising treatments for insomnia, some of which have been tested in Phase III clinical trials. These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis, says the study's abstract.

UT Southwestern researchers, working with colleagues in Japan, now have found that mice lacking orexins also have very thin and fragile bones that break easily because they have fewer cells called osteoblasts, which are responsible for building bones.

"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," explains Dr. Yihong Wan, according to the June 12, 2014 news release, "Proteins causing daytime sleepiness tied to bone formation, target for osteoporosis." Wan is an Assistant Professor of Pharmacology, the Virginia Murchison Linthicum Scholar in Medical Research, and senior author for the study.

Osteoporosis, the most common type of bone disease in which bones become fragile and susceptible to fracture, affects more than 10 million Americans

The disease, which disproportionately affects seniors and women, leads to more than 1.5 million fractures and some 40,000 deaths annually. In addition, the negative effects impact productivity, mental health, and quality of life. One in five people with hip fractures, for example, end up in nursing homes.

Orexins seem to play a dual role in the process: 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," says Dr. Wan, according to the news release. "It's remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues." Wan is a member of the Cecil H. and Ida Green Center for Reproductive Biology Sciences and UT Southwestern's Harold C. Simmons Comprehensive Cancer Center.

The central nervous system regulation is through OX2R, and therefore promotion of bone formation, was actually dominant over regulation through OX1R. So when the group examined mice lacking both OX1R and OX2R, they had very fragile bones with decreased bone formation. Similarly, when they assessed mice that expressed high levels of orexins, those mice had increased numbers of osteoblasts and enhanced bone formation.

The research was done in collaboration with Dr. Masashi Yanagisawa, adjunct professor of molecular genetics at UT Southwestern, a Howard Hughes Medical Institute investigator, and now with the International Institute for Integrative Sleep Medicine at the University of Tsukuba, in Japan. Dr. Yanagisawa's laboratory discovered orexins in 1998.

Other UT Southwestern researchers include lead author Dr. Wei Wei, postdoctoral researcher in Pharmacology; Dr. Xian-Jin Xie, Associate Professor of Clinical Sciences and the Simmons Cancer Center; Dr. Toshiyuki Motoike, Assistant Professor of Molecular Genetics; and Dr. Jing Y. Krzeszinski and Zixue Jin, postdoctoral researchers in Pharmacology.

The work was supported by the UT Southwestern Endowed Scholar Startup Fund, the National Institutes of Health, the Welch Foundation, the Howard Hughes Medical Institute, and the Japan Society for the promotion of Science. UT Southwestern's Harold C. Simmons Cancer Center is the only National Cancer Institute-designated cancer center in North Texas and one of just 66 NCI-designated cancer centers in the nation. It includes 13 major cancer care programs with a focus on treating the whole patient with innovative treatments, while fostering groundbreaking basic research that has the potential to improve patient care and prevention of cancer worldwide. In addition, the Center's education and training programs support and develop the next generation of cancer researchers and clinicians.

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