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 language | English |
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Pages (from-to) | 1138-1146 |
Number of pages | 9 |
Journal | Cell Death and Differentiation |
Volume | 13 |
Issue number | 7 |
DOIs | |
State | Published - Jul 2006 |
Bibliographical note
Funding Information:This study was supported by grant number 01-PJ5-PG1-01CH12-0002 from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (B-M Min).
Keywords
- GSH/GSSG ratio
- Osteoclastogenesis
- RANKL-dependent signaling
- Reactive oxygen species (ROS)
- Redox status