Vitamin E decreases bone mass by stimulating osteoclast fusion

Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption(1-3). Osteoclasts are multinucleated cells that are formed by mononuclear preosteoclast fusion(1,2,4,5). 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 alpha-tocopherol transfer protein (Ttpa(-/-) mice), a mouse model of genetic vitamin E deficiency(6), have high bone mass as a result of a decrease in bone resorption. Cell-based assays indicated that alpha-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(7-9). Indeed, the bone abnormality seen in Ttpa(-/-) mice was rescued by a Tm7sf4 transgene. Moreover, wild-type mice or rats fed an alpha-tocopherol-supplemented diet, which contains a comparable amount of alpha-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.