Vitamin E decreases bone mass by stimulating osteoclast fusion

Koji Fujita, Makiko Iwasaki, Hiroki Ochi, Toru Fukuda, Chengshan Ma, Takeshi Miyamoto, Kimitaka Takitani, Takako Negishi-Koga, Satoko Sunamura, Tatsuhiko Kodama, Hiroshi Takayanagi, Hiroshi Tamai, Shigeaki Kato, Hiroyuki Arai, Kenichi Shinomiya, Hiroshi Itoh, Atsushi Okawa, Shu Takeda

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Abstract

Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion. 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 deficiency, 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) promoter. 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.

Original languageEnglish
Pages (from-to)589-594
Number of pages6
JournalNature medicine
Volume18
Issue number4
DOIs
Publication statusPublished - 2012 Apr 1

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Fujita, K., Iwasaki, M., Ochi, H., Fukuda, T., Ma, C., Miyamoto, T., Takitani, K., Negishi-Koga, T., Sunamura, S., Kodama, T., Takayanagi, H., Tamai, H., Kato, S., Arai, H., Shinomiya, K., Itoh, H., Okawa, A., & Takeda, S. (2012). Vitamin E decreases bone mass by stimulating osteoclast fusion. Nature medicine, 18(4), 589-594. https://doi.org/10.1038/nm.2659