nitrophenols and deoxypyridinoline

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.

Topics: alpha-Tocopherol; Amino Acids; Animals; Apoptosis; Bone and Bones; Bone Resorption; Bromodeoxyuridine; Carrier Proteins; Cell Differentiation; Cell Proliferation; Cells, Cultured; Chromatin Immunoprecipitation; Disease Models, Animal; Gene Expression Regulation; Humans; In Situ Nick-End Labeling; Macrophage Colony-Stimulating Factor; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Microphthalmia-Associated Transcription Factor; Mitogen-Activated Protein Kinase 14; Nitrophenols; Osteoclasts; Osteocytes; RANK Ligand; Rats; RNA, Small Interfering; Signal Transduction; Tomography, X-Ray Computed; Transfection; Vitamin E; Vitamin E Deficiency; Vitamins