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Central control of bone remodeling by neuromedin U

Abstract

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 leptin3,4,5 inhibits bone formation through a hypothalamic relay6,7 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 mechanisms8,9. 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 formation6,7 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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Figure 1: High bone mass in Nmu−/− mice due to increased bone formation.
Figure 2: Absence of NMU's direct effect on osteoblasts; decrease in bone mass by NMU i.c.v.
Figure 3: Leptin does not eliminate high bone mass in Nmu−/− mice.
Figure 4: Sympathetic activation does not rescue high bone mass in Nmu−/− mice.

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Acknowledgements

We thank G. Karsenty, M. Patel and P. Ducy for critical review of the manuscript and for helpful discussions; K. Nakao, M. Noda, T. Matsumoto and S. Ito for insightful suggestions; P. Barrett (Rowett Research Institute, UK) for providing a plasmid for the Cartpt probe; and J. Chen, M. Starbuck, S. Sunamura, H. Murayama, H. Yamato, and M. Kajiwara for technical assistance. This work was supported by grant-in-aid for scientific research from the Japan Society for the Promotion of Science, a grant for the 21st Century Center of Excellence program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Ono Medical Research Foundation, Yamanouchi Foundation for Research on Metabolic Disorders, Kanae Foundation for the Promotion of the Medical Science and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan.

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Authors and Affiliations

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Contributions

S. Sato conducted most of the experiments. K. Kangawa and M. Kojima generated Nmu−/− mice. R. Hanada and T. Ida conducted in vitro experiments. S. Fukumoto, Y. Takeuchi and T. Fujita contributed by conducting dual X-ray absorptiometry analyses and providing suggestions on the project. M. Iwasaki prepared the constructs. A. Kimura performed i.c.v. infusion experiments. H. Inose conducted μCT analyses. T. Matsumoto and S. Kato conducted histological analyses for brain tissue. T. Abe and M. Mieda performed in situ hybridization analysis. S. Takeda and K. Shinomiya designed the project. S. Takeda supervised the project and wrote most of the manuscript.

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Correspondence to Shu Takeda.

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Supplementary Figs. 1–7 (PDF 5011 kb)

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Sato, S., Hanada, R., Kimura, A. et al. Central control of bone remodeling by neuromedin U. Nat Med 13, 1234–1240 (2007). https://doi.org/10.1038/nm1640

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