Central control of bone remodeling by neuromedin U

doi:doi:10.1038/nm1640

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts¹ and bone resorption by osteoclasts². The demonstration that the anorexigenic hormone leptin^3,^4,⁵ inhibits bone formation through a hypothalamic relay^6,⁷ suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms^8,⁹. Here we show that Nmu-deficient (Nmu^-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system–mediated inhibition of bone formation^6,⁷ was abolished in Nmu^-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action¹⁰, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.

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