Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption1,2,3. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion1,2,4,5. Fat-soluble vitamins such as vitamin D are pivotal in maintaining skeletal integrity. However, the role of vitamin E in bone remodeling is unknown. Here, we show that mice deficient in α-tocopherol transfer protein (Ttpa−/− mice), a mouse model of genetic vitamin E deficiency6, have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that α-tocopherol stimulated osteoclast fusion, independent of its antioxidant capacity, by inducing the expression of dendritic-cell–specific transmembrane protein, an essential molecule for osteoclast fusion, through activation of mitogen-activated protein kinase 14 (p38) and microphthalmia-associated transcription factor, as well as its direct recruitment to the Tm7sf4 (a gene encoding DC-STAMP) promoter7,8,9. Indeed, the bone abnormality seen in Ttpa−/− mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an α-tocopherol–supplemented diet, which contains a comparable amount of α-tocopherol to supplements consumed by many people, lost bone mass. These results show that serum vitamin E is a determinant of bone mass through its regulation of osteoclast fusion.
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We thank G. Karsenty, R. Baron and S. Tanaka for discussions; Y. Hotta, K. Miyamoto, H. Inose, S. Sato, A. Kimura, R. Xu and C. Xu for technical assistance; and T. Kitamura (Divisions of Cellular Therapy and Hematopoietic Factors, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan) and I. Takada (Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan) for plasmids. This work was supported by the Funding Program for Next Generation World-Leading Researchers (NEXT Program), grant-in-aid for scientific research from the Japan Society for the Promotion of Science, a grant for Global Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and a Takeda Scientific Foundation grant.
The authors declare no competing financial interests.
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Fujita, K., Iwasaki, M., Ochi, H. et al. Vitamin E decreases bone mass by stimulating osteoclast fusion. Nat Med 18, 589–594 (2012). https://doi.org/10.1038/nm.2659
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