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

被引:69
作者
Huh, Y-J
Kim, J-M
Kim, H.
Song, H.
So, H.
Lee, S. Y.
Kwon, S. B.
Kim, H. J.
Kim, H-H
Lee, S. H.
Choi, Y.
Chung, S-C
Jeong, D-w
Min, B-M
机构
[1] Seoul Natl Univ, Coll Dent, Inst Dent Res, Dept Oral Biochem & Craniomaxillofacial Recontruc, Seoul 110749, South Korea
[2] Seoul Natl Univ, Coll Dent, IBEC, Seoul 110749, South Korea
[3] Korea Adv Inst Sci & Technol, Dept Sci Biol, Taejon 305701, South Korea
[4] Wonkwang Univ, Sch Med, Vestibulorcochlear Res Ctr, Iksan 570749, South Korea
[5] Ewha Womans Univ, Div Mol Life Sci, Seoul 120750, South Korea
[6] Ewha Womans Univ, Ctr Cell Signalling Res, Seoul 120750, South Korea
[7] Seoul Natl Univ, Coll Dent, Dept Cell & Dev Biol, Seoul 110749, South Korea
[8] Univ Penn, Abramson Canc Res Inst, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[9] Seoul Natl Univ, Coll Dent, Dept Oral Med & Oral Diag, Seoul 110749, South Korea
关键词
D O I
10.1038/sj.cdd.4401793
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-kappa 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.
引用
收藏
页码:1138 / 1146
页数:9
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