IBMS BoneKEy | BoneKEy Watch
Orexin acts via two receptors to regulate bone mass
DOI:10.1038/bonekey.2014.100
Orexin is a neuropeptide that acts through two receptors, OX1R and OX2R, to stimulate appetite, arousal, energy expenditure and reward. Wei et al. investigated its impact on bone mass.
Orexin knockout mice (OX-KO) had a 30% lower trabecular bone volume to tissue volume ratio compared to wild type. Serum levels of N-terminal propeptide type 1 procollagen, an established bone formation marker, were 30% lower. OX1R was expressed in bone tissue while OX2R was not; OX1R activation appears to inhibit differentiation of osteoblasts from mesenchymal stem cells, favoring adipogenesis in the bone marrow.
The high bone mass phenotype of OX1R-KO mice contrasted with the low bone mass phenotype of OX2R-KO mice, suggesting that OX1R is involved in local regulation of bone mass but that interaction between orexin and OX2R mediates central regulation of bone mass accrual.
Two levels of control are therefore in place: OX1R inhibitors differentiation of MSCs into osteoblasts through suppression of ghrelin expression in bone while OX2F enhances bone formation through suppression of serum leptin production by the sympathetic nerves.
Editor’s comment: The authors demonstrate that orexin is an important regulator of bone formation and that its central action is dominant. This raises questions about the OX1R, OX2R and joint OX1R2R antagonists currently in development for the treatment of insomnia. Treatment with the two latter drugs may adversely affect bone mass, while OX1R antagonists may have a place in the treatment of osteoporosis.
This work is licensed under a
Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.