Central control of bone remodeling by neuromedin U.
Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay 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. 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 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 action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.
Sato
Shingo
S
Department of Orthopaedic Surgery, Graduate School, 21st Century Center of Excellence Program, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8519, Japan.
Hanada
Reiko
R
Kimura
Ayako
A
Abe
Tomomi
T
Matsumoto
Takahiro
T
Iwasaki
Makiko
M
Inose
Hiroyuki
H
Ida
Takanori
T
Mieda
Michihiro
M
Takeuchi
Yasuhiro
Y
Fukumoto
Seiji
S
Fujita
Toshiro
T
Kato
Shigeaki
S
Kangawa
Kenji
K
Kojima
Masayasu
M
Shinomiya
Ken-ichi
K
Takeda
Shu
S
D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D020738:Leptin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009479:Neuropeptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D012737:Sex Factors; D013564:Sympathetic Nervous System / Q000378:metabolism; D014057:Tomography, X-Ray Computed
D020738:Leptin; D009479:Neuropeptides; C056900:neuromedin U