1. ¹Department of Oral Biochemistry and Craniomaxillofacial Reconstructive Science, Dental Research Institute, Seoul National University College of Dentistry, Seoul 110-749, Korea
2. ²IBEC, Seoul National University College of Dentistry, Seoul 110-749, Korea
3. ³Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
4. ⁴Vestibulorcochlear Research Center, Wonkwang University School of Medicine, Chonbuk, Ik-San 570-749, Korea
5. ⁵Division of Molecular Life Sciences and the Center for Cell Signaling Research, Ewha Woman's University, Seoul 120-750, Korea
6. ⁶Department of Cell and Developmental Biology, Seoul National University College of Dentistry, Seoul 110-749, Korea
7. ⁷Department of Pathology and Laboratory Medicine, Abramson Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA
8. ⁸Department of Oral Medicine and Oral Diagnosis, Seoul National University College of Dentistry, Seoul 110-749, Korea
9. ⁹BK21 HLS, Seoul National University, Seoul 110-749, Korea
10. ¹⁰These authors contributed equally to this work

Correspondence: D-w Jeong, BK21 HLS, Seoul National University, 28 Yeonkun-Dong, Chongno-Ku, Seoul 110-749, Korea. Tel: +82-2-740-8664; Fax: +82-2-740-8665; E-mail: dwjeong@snu.ac.kr; B-M Min, Department of Oral Biochemistry and Craniomaxillofacial Reconstructive Science, Seoul National University College of Dentistry, 28 Yeonkun-Dong, Chongno-Ku, Seoul 110-749, Korea. Tel: +82-2-740-8661; Fax: +82-2-740-8665; E-mail: bmmin@snu.ac.kr

Received 28 December 2004; Revised 4 August 2005; Accepted 25 August 2005; Published online 14 October 2005.

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.