University of Texas Southwestern Medical Center professor Dr. Yihong Wan is researching proteins known as orexins, which are associated with spontaneous daytime sleepiness, play a dual role in the skeleton and can influence osteoporosis onset and progression.
As reported by Dr. Wan and lead author Wei Wei in the journal Cell Metabolism, orexins directly influence osteoblast differentiation and regulate the circulating hormones leptin and ghrelin. The two hormones have opposing effects on bone formation. “We were very intrigued by this yin-yang-style dual regulation,” said Dr. Wan. “It is remarkable that orexins manage to regulate bone formation by using two different receptors located in two different tissues.”
In bone, orexins stimulate orexin receptor 1 (OX1R), which decreases ghrelin levels and hinders osteoblast differentiation in favor of adipocyte production. In the brain, orexins activate orexin receptor 2 (OX2R), which decreases leptin and promotes bone formation. Consequently, a strategy to treat osteoporosis could involve inhibiting OX1R or activating OX2R.
In the research team’s mouse models, it was determined OX2R dominated bone regulation over OX1R. Overexpression of orexins increased osteoblast number and activity. Therefore, orexins seem to favor bone formation.
“We are hoping that we might be able to take advantage of the already available orexin-targeting small molecules to potentially treat osteoporosis.” A number of orexins have been tested in Phase 3 clinical trials for the treatment of insomnia, which gives evidence orexins might be safe to use in patients. However, further validation would be required, as well as investigations of their efficacy in treating osteoporosis.
Orexins were originally discovered at UT Southwestern over 15 years ago. They have previously been associated with arousal, appetite, reward, energy expenditure, and wakefulness. Dr. Wan’s study is the first to show orexins influence bone production and can contribute to osteoporosis.
“Osteoporosis is highly prevalent, especially among post-menopausal women,” said Dr. Wan in a news release. Osteoporosis is characterized by weak, thin bones due to age- or hormone-related bone loss. Whereas bone loss is normally compensated for by bone-building osteoblast cells, in osteoporosis, individuals have fewer or less-active osteoblasts that cannot make up for lost bone. Targeting orexins may improve the lives of the over 10 million Americans affected by osteoporosis.