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Vitamin E decreases bone mass by stimulating osteoclast fusion

An Erratum to this article was published on 07 September 2012

This article has been updated

Abstract

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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Figure 1: Serum vitamin E regulates bone resorption.
Figure 2: Vitamin E stimulates osteoclast fusion independent of its antioxidant activity.
Figure 3: α-tocopherol regulates osteoclast fusion through DC-STAMP.
Figure 4: α-tocopherol decreases bone mass through p38α and Mitf.

Change history

  • 04 May 2012

     In the version of this article initially published, it was incorrectly stated that the mice were fed a diet supplemented with α-tocopherol at 600 mg per kg of body weight. Instead, the food itself contained 600 mg of α-tocopherol per kg. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

K.F. conducted most of the experiments. M.I., H.O. and C.M. conducted mice analyses. T.F. and S.S. conducted in vitro experiments. T.M. provided DC-STAMP–related mice. K.T. and H. Tamai conducted the analyses of vitamin E serum concentrations. T.N.-K. performed western blots. H.A. provided Ttpa−/− mice. T.K. and H. Takayanagi conducted gene expression analyses. S.T., K.S., A.O. and H.I. designed the project. S.T. supervised the project and wrote most of the manuscript. S.K. designed the project.

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Correspondence to Shu Takeda.

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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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