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Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis

Nature Medicine volume 15, pages 1066–1071 (2009)Cite this article

Abstract

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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Figure 1: IRF-8 inhibits osteoclastogenesis in BMMs stimulated with M-CSF and RANKL.
Figure 2: Irf8−/− mice show severe osteoporosis due to enhanced osteoclast formation.
Figure 3: IRF-8 deficiency or RNA interference–mediated silencing in osteoclast precursors leads to enhanced osteoclast formation.
Figure 4: IRF-8 inhibits NFATc1 transcriptional activity and expression, and reduced IRF-8 expression may contribute to pathological bone destruction.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Biochemistry, School of Dentistry, Showa University, Shinagawa, Tokyo, Japan

    Baohong Zhao, Masamichi Takami, Atsushi Yamada, Xiaogu Wang & Ryutaro Kamijo

  2. Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York, USA

    Baohong Zhao, Xiaoyu Hu & Lionel B Ivashkiv

  3. Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    Takako Koga & Hiroshi Takayanagi

  4. Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo, Japan

    Takako Koga & Hiroshi Takayanagi

  5. Department of Medicine, Weill Cornell Medical College, New York, New York, USA

    Xiaoyu Hu & Lionel B Ivashkiv

  6. Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Tomohiko Tamura & Keiko Ozato

  7. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Yongwon Choi

  8. Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA

    Lionel B Ivashkiv

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  1. Baohong Zhao
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Contributions

B.Z. performed most of the experiments with substantial assistance from M.T. X.W. conducted the histological analysis. A.Y., T.K., X.H. and T.T. assisted with the experiments. K.O. provided the Irf8−/− mice. B.Z. and M.T. designed the project and wrote the manuscript. Y.C. provided recombinant RANKL and contributed to manuscript preparation. L.B.I. oversaw the bone marrow chimera and human cell experiments and contributed to manuscript revision. H.T. oversaw the inflammatory bone destruction experiments and provided crucial advice for the experiments. M.T. and R.K. supervised the project.

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Correspondence to Masamichi Takami.

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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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