The investigators noted that orexin knockout mice exhibit a similar bone phenotype to the OX2R knockout mice, suggesting that the OX2R-mediated central control dominates over the OX1R-mediated peripheral regulation. To investigate this hypothesis further, they examined OX1R2R double null mice and found these mice also exhibit low bone mass.
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In contrast, and as predicted, orexin-overexpressing transgenic mice had enhanced bone mass, which reinforced the understanding that OX2R-mediated central regulation is dominant to OX1R-mediated peripheral modulation of bone cell differentiation.
Orexin as Therapeutic Target
Wei and colleagues conclude by suggesting that orexin be considered a potential therapeutic target for osteoporosis. In particular, they suggest that OX2R-specific agonists may be effective bone anabolic therapeutics.
The authors expand on the therapeutic implications for orexin by reminding the reader that orexin is involved in more than just bone remodeling. Humans who lack orexin have behavioral abnormalities, including sleep and mood disorders. Orexin deficiency is also associated with obesity and hyperphagia. Orexin antagonists may, therefore, be effective for the treatment of insomnia and other orexin-associated disorders as well. (posted 7/3/14)
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
1. Wei W, Motoike T, Krzeszinski JY, et al. Orexin Regulates Bone Remodeling via a Dominant Positive Central Action and a Subordinate Negative Peripheral Action. 2014. Cell Metab. Jun 3;19(6):927-940.