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Regulation of osteoclast differentiation by the redox-dependent modulation of nuclear import of transcription factors
Cited 56 time in
Web of Science
Cited 57 time in Scopus
- Authors
- Issue Date
- 2006
- Publisher
- Nature Publishing Group
- Citation
- Cell Death and Differentiation 13:1138-1146
- Keywords
- reactive oxygen species (ROS) ; redox status ; GSH/GSSG ratio ; osteoclastogenesis ; RANKL-dependent signaling
- 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 -glutamylcysteinyl synthetase modifier gene. Glutathione depletion by L-buthionine-(S,R)-sulfoximine (BSO) was found to inhibit osteoclastogenesis by blocking nuclear import of NF-B 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.
- ISSN
- 1350-9047
- Language
- English
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