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

Y. J. Huh, J. M. Kim, H. Kim, H. Song, H. So, S. Y. Lee, S. B. Kwon, H. J. Kim, H. H. Kim, S. H. Lee, Y. Choi, S. C. Chung, D. W. Jeong, B. M. Min

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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 γ-glutamylcysteinyl synthetase modifier gene. Glutathione depletion by L-buthionine-(S,R)-sulfoximine (BSO) was found to inhibit osteoclastogenesis by blocking nuclear import of NF-κB 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.

Original languageEnglish
Pages (from-to)1138-1146
Number of pages9
JournalCell Death and Differentiation
Volume13
Issue number7
DOIs
StatePublished - Jul 2006

Keywords

  • GSH/GSSG ratio
  • Osteoclastogenesis
  • RANKL-dependent signaling
  • Reactive oxygen species (ROS)
  • Redox status

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