Vitamin E decreases bone mass by stimulating osteoclast fusion

Nat Med. 2012 Mar 4;18(4):589-94. doi: 10.1038/nm.2659.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / blood
  • Animals
  • Apoptosis / drug effects
  • Bone Resorption / diet therapy*
  • Bone Resorption / etiology
  • Bone Resorption / genetics
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / drug effects*
  • Bone and Bones / pathology
  • Bromodeoxyuridine / metabolism
  • Carrier Proteins / genetics
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Humans
  • In Situ Nick-End Labeling
  • Macrophage Colony-Stimulating Factor / metabolism
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Nitrophenols / metabolism
  • Osteoclasts / drug effects*
  • Osteocytes / drug effects
  • Osteocytes / metabolism
  • RANK Ligand / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tomography, X-Ray Computed
  • Transfection
  • Vitamin E / administration & dosage*
  • Vitamin E / blood
  • Vitamin E Deficiency / complications
  • Vitamin E Deficiency / diet therapy
  • Vitamin E Deficiency / genetics
  • Vitamin E Deficiency / pathology*
  • Vitamins / administration & dosage*
  • Vitamins / blood
  • alpha-Tocopherol / administration & dosage
  • alpha-Tocopherol / blood

Substances

  • Amino Acids
  • Carrier Proteins
  • Dcstamp protein, mouse
  • Membrane Proteins
  • Microphthalmia-Associated Transcription Factor
  • Nitrophenols
  • RANK Ligand
  • RNA, Small Interfering
  • Vitamins
  • alpha-tocopherol transfer protein
  • Vitamin E
  • Macrophage Colony-Stimulating Factor
  • deoxypyridinoline
  • Mitogen-Activated Protein Kinase 14
  • Bromodeoxyuridine
  • alpha-Tocopherol
  • 4-nitrophenol