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, Soo Young Lee

Research output: Contribution to journalArticlepeer-review

762 Scopus citations


Signaling by receptor activator of NF-κB (nuclear factor-κB) 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-acetyl-cysteine (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.

Original languageEnglish
Pages (from-to)852-859
Number of pages8
Issue number3
StatePublished - 1 Aug 2005


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