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Blood, 1 August 2005, Vol. 106, No. 3, pp. 852-859.
Prepublished online as a Blood First Edition Paper on April 7, 2005; DOI 10.1182/blood-2004-09-3662.
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Submitted September 21, 2004
Accepted March 30, 2005
A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation
Na Kyung Lee, Young Geum Choi, Ji Youn Baik, Song Yi Han, Dae-won Jeong, Yun Soo Bae, Nacksung Kim, and Soo Young Lee*
Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea, Republic of
BK21 HLS, Seoul National University, Seoul, Korea, Republic of
Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Korea, Republic of
* Corresponding author; email: leesy{at}ewha.ac.kr.
Signaling by receptor activator of NF- B ligand (RANKL) is essential for differentiation of bone marrow monocytes/macrophage lineage cells (BMMs) into osteoclasts. Here, we show RANKL stimulation of BMMs transiently increased the intracellular level of reactive oxygen species (ROS) through a signaling cascade involving TNF receptor-associated factor (TRAF) 6, Rac1, and NADPH oxidase (Nox) 1. A deficiency in TRAF6 or expression of a dominant interfering mutant of TRAF6 blocks RANKL-mediated ROS production. Application of N-acetylcysteine (NAC) or blocking the activity of Nox, a protein leading to the formation of ROS, with diphenylene iodonium (DPI) inhibits the responses of BMMs to RANKL, including ROS production, activation of c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), and osteoclast differentiation. Moreover, both RANKL-mediated ROS production and osteoclast differentiation were completely blocked in precursors depleted of Nox1 activity by RNA interference or by expressing a dominant negative mutant of Rac1. Together, these results indicate that ROS act as an intracellular signal mediator for osteoclast differentiation.
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