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RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β


Osteoclasts are cells of monocyte/macrophage origin that erode bone matrix: regulation of their differentiation is central to the understanding of the pathogenesis and treatment of bone diseases such as osteoporosis1,2. Signalling by RANKL (receptor activator of NF-κB ligand), also known as Tnfsf11, is essential for the induction of osteoclast differentiation3,4,5, and it must be strictly regulated to maintain bone homeostasis. But it is not known whether RANKL signalling to the cell interior is linked to any regulatory mechanisms. Here we show that RANKL induces the interferon-β (IFN-β) gene in osteoclast precursor cells, and that IFN-β inhibits the differentiation by interfering with the RANKL-induced expression of c-Fos, an essential transcription factor for the formation of osteoclasts. This IFN-β gene induction mechanism is distinct from that induced by virus, and is dependent on c-Fos itself. Thus an autoregulatory mechanism operates—the RANKL-induced c-Fos induces its own inhibitor. The importance of this regulatory mechanism for bone homeostasis is emphasized by the observation that mice deficient in IFN-β signalling exhibit severe osteopenia (loss of bone mass) accompanied by enhanced osteoclastogenesis. Our study places the IFN-β system in a new context, and may offer a molecular basis for the treatment of bone diseases.

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Figure 1: Bone phenotype of mice deficient in IFN-α/β signalling.
Figure 2: Selective induction of IFN-β mRNA by RANKL and the function of IFN-β in vivo and in vitro.
Figure 3: IFN-β inhibits RANKL signalling by suppressing the c-Fos protein expression.
Figure 4: c-Fos-dependent induction of IFN-β by RANKL.
Figure 5: Therapeutic effect of IFN-β and its novel signalling cross-talk with RANKL.


  1. Manolagas, S. C. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr. Rev. 21, 115–137 (2000).

    CAS  PubMed  Google Scholar 

  2. Rodan, G. A. & Martin, T. J. Therapeutic approaches to bone diseases. Science 289, 1508–1514 (2000).

    ADS  CAS  Article  Google Scholar 

  3. Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3660 (1998).

    ADS  CAS  Article  Google Scholar 

  4. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    ADS  CAS  Article  Google Scholar 

  5. Suda, T. et al. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 20, 345–357 (1999).

    CAS  Article  Google Scholar 

  6. Takayanagi, H. et al. Involvement of receptor activator of nuclear factor κB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 43, 259–269 (2000).

    CAS  Article  Google Scholar 

  7. Takayanagi, H. et al. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).

    ADS  CAS  Article  Google Scholar 

  8. Matsuo, K. et al. Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nature Genet. 24, 184–187 (2000).

    CAS  Article  Google Scholar 

  9. Wagner, E. F. & Karsenty, G. Genetic control of skeletal development. Curr. Opin. Genet. Dev. 11, 527–532 (2001).

    CAS  Article  Google Scholar 

  10. Lomaga, M. A. et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev. 13, 1015–1024 (1999).

    CAS  Article  Google Scholar 

  11. Naito, A. et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4, 353–362 (1999).

    CAS  Article  Google Scholar 

  12. Wang, Z. Q. et al. Bone and haematopoietic defects in mice lacking c-fos. Nature 360, 741–745 (1992).

    ADS  CAS  Article  Google Scholar 

  13. Grigoriadis, A. E. et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266, 443–448 (1994).

    ADS  CAS  Article  Google Scholar 

  14. Roodman, G. D. Cell biology of the osteoclast. Exp. Hematol. 27, 1229–1241 (1999).

    CAS  Article  Google Scholar 

  15. Simonet, W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).

    CAS  Article  Google Scholar 

  16. Bucay, N. et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 12, 1260–1268 (1998).

    CAS  Article  Google Scholar 

  17. Müller, U. et al. Functional role of type I and type II interferons in antiviral defense. Science 264, 1918–1921 (1994).

    ADS  Article  Google Scholar 

  18. Takaoka, A. et al. Cross talk between interferon-γ and -α/β signaling components in caveolar membrane domains. Science 288, 2357–2360 (2000).

    ADS  CAS  Article  Google Scholar 

  19. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    CAS  Article  Google Scholar 

  20. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. & Schreiber, R. D. How cells respond to interferons. Annu. Rev. Biochem. 67, 227–264 (1998).

    CAS  Article  Google Scholar 

  21. Samuel, C. E. The eIF-2 α protein kinases, regulators of translation in eukaryotes from yeasts to humans. J. Biol. Chem. 268, 7603–7606 (1993).

    CAS  PubMed  Google Scholar 

  22. Yang, Y. L. et al. Deficient signaling in mice devoid of double-stranded RNA-dependent protein kinase. EMBO J. 14, 6095–6106 (1995).

    CAS  Article  Google Scholar 

  23. Wathelet, M. G. et al. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-β enhancer in vivo. Mol. Cell 1, 507–518 (1998).

    CAS  Article  Google Scholar 

  24. Sato, M. et al. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13, 539–548 (2000).

    CAS  Article  Google Scholar 

  25. Takayanagi, H. et al. Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J. Clin. Invest. 104, 137–146 (1999).

    CAS  Article  Google Scholar 

  26. Ogata, N. et al. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J. Clin. Invest. 105, 935–943 (2000).

    CAS  Article  Google Scholar 

  27. Matsuyama, T. et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 75, 83–97 (1993).

    CAS  Article  Google Scholar 

  28. Kimura, T. et al. Essential and non-redundant roles of p48 (ISGF3 γ) and IRF-1 in both type I and type II interferon responses, as revealed by gene targeting studies. Genes Cells 1, 115–124 (1996).

    CAS  Article  Google Scholar 

  29. Meraz, M. A. et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84, 431–442 (1996).

    CAS  Article  Google Scholar 

  30. Hida, S. et al. CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-α/β signaling. Immunity 13, 643–655 (2000).

    CAS  Article  Google Scholar 

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We thank H. Murayama and Kureha Chemical Industries for technical assistance, and E. Barsoumian, A. Bichl, M. Radolf, A. Takaoka, K. Honda, M. Asagiri, N. Hata, S. Muraki, M. Isobe, S. Kano and I. Kawai for discussion and assistance. This work was supported in part by a grant for Advanced Research on Cancer from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a research fellowship of the Japan Society for the Promotion of Science for Young Scientists, Health Sciences Research Grants from the Ministry of Health and Welfare of Japan, the Japan Orthopaedics and Traumatology Foundation, and PRESTO, Japan Science and Technology Corporation.

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Correspondence to Tadatsugu Taniguchi.

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Takayanagi, H., Kim, S., Matsuo, K. et al. RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-β. Nature 416, 744–749 (2002).

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