Regulation of osteoclast differentiation by the redox-dependent modulation of nuclear import of transcription factors

Cell Death Differ. 2006 Jul;13(7):1138-46. doi: 10.1038/sj.cdd.4401793. Epub 2005 Oct 14.

Abstract

This study sought to characterize the reduced glutathione (GSH)/oxidized GSSG ratio during osteoclast differentiation and determine whether changes in the intracellular redox status regulate its differentiation through a RANKL-dependent signaling pathway. A progressive decrease of the GSH/GSSG ratio was observed during osteoclast differentiation, and the phenomenon was dependent on a decrease in total glutathione via downregulation of expression of the gamma-glutamylcysteinyl synthetase modifier gene. Glutathione depletion by L-buthionine-(S,R)-sulfoximine (BSO) was found to inhibit osteoclastogenesis by blocking nuclear import of NF-kappaB and AP-1 in RANKL-propagated signaling and bone pit formation by increasing BSO concentrations in mature osteoclasts. Furthermore, intraperitoneal injection of BSO in mice resulted in an increase in bone density and a decrease of the number of osteoclasts in bone. Conversely, glutathione repletion with either N-acetylcysteine or GSH enhanced osteoclastogenesis. These findings indicate that redox status decreases during osteoclast differentiation and that this modification directly regulates RANKL-induced osteoclastogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Buthionine Sulfoximine / pharmacology
  • Carrier Proteins / pharmacology
  • Cell Differentiation / physiology*
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Glutathione Disulfide / metabolism
  • Immunoblotting
  • Membrane Glycoproteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • NF-kappa B / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Oxidation-Reduction / drug effects
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism*

Substances

  • Carrier Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Transcription Factor AP-1
  • Transcription Factors
  • Buthionine Sulfoximine
  • Glutamate-Cysteine Ligase
  • Glutathione
  • Glutathione Disulfide