title: Vitamin E decreases bone mass by stimulating osteoclast fusion.
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.
authors.affiliation: Department of Orthopedic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Makiko
authors.initials: M
authors.lastname: Iwasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ochi
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Chengshan
authors.initials: C
authors.lastname: Ma
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Takitani
authors.forename: Takako
authors.initials: T
authors.lastname: Negishi-Koga
authors.forename: Satoko
authors.initials: S
authors.lastname: Sunamura
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamai
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shinomiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000178:diet therapy* / Q000209:etiology / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014057:Tomography, X-Ray Computed; D014162:Transfection; D014810:Vitamin E / Q000008:administration & dosage* / Q000097:blood; D014811:Vitamin E Deficiency / Q000150:complications / Q000178:diet therapy / Q000235:genetics / Q000473:pathology*; D014815:Vitamins / Q000008:administration & dosage* / Q000097:blood; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000097:blood
chemical_list: D000596:Amino Acids; D002352:Carrier Proteins; C501590:Dcstamp protein, mouse; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D009596:Nitrophenols; D053245:RANK Ligand; D034741:RNA, Small Interfering; D014815:Vitamins; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D016173:Macrophage Colony-Stimulating Factor; C036020:deoxypyridinoline; D048308:Mitogen-Activated Protein Kinase 14; D001973:Bromodeoxyuridine; D024502:alpha-Tocopherol; C024836:4-nitrophenol