Bone metabolism results from a balance between osteoclast-driven bone resorption and osteoblast-mediated bone formation. Diseases such as periodontitis and rheumatoid arthritis are characterized by increased bone destruction due to enhanced osteoclastogenesis1,2. Here we report that interferon regulatory factor-8 (IRF-8), a transcription factor expressed in immune cells, is a key regulatory molecule for osteoclastogenesis. IRF-8 expression in osteoclast precursors was downregulated during the initial phase of osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL), which is encoded by the Tnfsf11 gene. Mice deficient in Irf8 showed severe osteoporosis, owing to increased numbers of osteoclasts, and also showed enhanced bone destruction after lipopolysaccharide (LPS) administration. Irf8−/− osteoclast precursors underwent increased osteoclastogenesis in response to RANKL and tumor necrosis factor-α (TNF-α). IRF-8 suppressed osteoclastogenesis by inhibiting the function and expression of nuclear factor of activated T cells c1 (NFATc1). Our results show that IRF-8 inhibits osteoclast formation under physiological and pathological conditions and suggest a model where downregulation of inhibitory factors such as IRF-8 contributes to RANKL-mediated osteoclastogenesis.
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Gene Expression Omnibus
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We are grateful to M. Asagiri for technical assistance. We thank T. Kitamura (University of Tokyo) for providing the retrovirus expression system. We also thank A. Mochizuki and all members of the Department of Biochemistry, School of Dentistry, Showa University for valuable discussions. This work is supported in part by the High-Tech Research Center Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology, Japan, 2005-2009, by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (20390474 to M.T.) and by grants from the US National Institutes of Health (AR053843 and DE19381 to Y.C. and DE019420 and AR46713 to L.B.I.).
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Zhao, B., Takami, M., Yamada, A. et al. Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis. Nat Med 15, 1066–1071 (2009). https://doi.org/10.1038/nm.2007
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