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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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HEMATOPOIESIS
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
From the Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Korea; Brain Korea 21, Human Life Sciences, Seoul National University, Seoul, Korea; and the Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Korea.
Signaling by receptor activator of NF- B (nuclear factor-B) ligand (RANKL) is essential for differentiation of bone marrow monocyte-macrophage lineage (BMM) cells into osteoclasts. Here, we show RANKL stimulation of BMM cells transiently increased the intracellular level of reactive oxygen species (ROS) through a signaling cascade involving TNF (tumor necrosis factor) receptor-associated factor (TRAF) 6, Rac1, and NADPH (nicotinamide adenine dinucleotide phosphate) 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 BMM cells to RANKL, including ROS production, activation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein (MAP) kinase, 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 ROSs act as an intracellular signal mediator for osteoclast differentiation.
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