Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ


Bone resorption is regulated by the immune system1,2, where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-κB ligand), a member of the tumour-necrosis factor family that is essential for osteoclastogenesis, may contribute to pathological conditions, such as autoimmune arthritis3,4. However, whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown. Here we show that T-cell production of interferon (IFN)-γ strongly suppresses osteoclastogenesis by interfering with the RANKL–RANK signalling pathway. IFN-γ induces rapid degradation of the RANK adapter protein, TRAF6 (tumour necrosis factor receptor-associated factor 6), which results in strong inhibition of the RANKL-induced activation of the transcription factor NF-κB and JNK. This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells, which indicates that TRAF6 is the target critical for the IFN-γ action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-γ-induced activation of the ubiquitin–proteasome system. Our study shows that there is cross-talk between the tumour necrosis factor and IFN families of cytokines, through which IFN-γ provides a negative link between T-cell activation and bone resorption. Our results may offer a therapeutic approach to treat the inflammation-induced tissue breakdown.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: T-cell-mediated regulation of osteoclastogenesis by IFN-γ.
Figure 2: Inhibition of RANKL-induced osteoclastogenesis by IFN-γ through Stat1 activation pathway.
Figure 3: Inhibition of RANKL signalling by IFN-γ through downregulation of TRAF6.
Figure 4: Involvement of the ubiquitin–proteasome pathway in the acceleration of TRAF6 proteolysis.


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

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

    Article  ADS  CAS  Google Scholar 

  5. 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).

    Article  CAS  Google Scholar 

  6. Horwood, N. J. et al. Activated T lymphocytes support osteoclast formation in vitro. Biochem. Biophys. Res. Commun. 265, 144–150 (1999).

    Article  CAS  Google Scholar 

  7. Takahashi, N., Mundy, G. R. & Roodman, G. D. Recombinant human interferon-γ inhibits formation of human osteoclast-like cells. J. Immunol. 137, 3544–3549 (1986).

    CAS  PubMed  Google Scholar 

  8. Udagawa, N. et al. Interleukin-18 (interferon-γ-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-γ to inhibit osteoclast formation. J. Exp. Med. 185, 1005–1012 (1997).

    Article  CAS  Google Scholar 

  9. Ukai, T., Hara, Y. & Kato, I. Effects of T cell adoptive transfer into nude mice on alveolar bone resorption induced by endotoxin. J. Periodontal. Res. 31, 414–422 (1996).

    Article  CAS  Google Scholar 

  10. Chiang, C. Y., Kyritsis, G., Graves, D. T. & Amar, S. Interleukin-1 and tumor necrosis factor activities partially account for calvarial bone resorption induced by local injection of lipopolysaccharide. Infect. Immun. 67, 4231–4236 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).

    Article  ADS  CAS  Google Scholar 

  12. Manoury-Schwartz, B. et al. High susceptibility to collagen-induced arthritis in mice lacking IFN-γ receptors. J. Immunol. 158, 5501–5506 (1997).

    CAS  PubMed  Google Scholar 

  13. Vermeire, K. et al. Accelerated collagen-induced arthritis in IFN-γ receptor-deficient mice. J. Immunol. 158, 5507–5513 (1997).

    CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Taniguchi, T., Lamphier, M. S. & Tanaka, N. IRF-1: the transcription factor linking the interferon response and oncogenesis. Biochim. Biophys. Acta 1333, M9–M17 (1997).

    CAS  PubMed  Google Scholar 

  16. Wong, B. R. et al. The TRAF family of signal transducers mediates NF-κB activation by the TRANCE receptor. J. Biol. Chem. 273, 28355–28359 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Baumeister, W., Walz, J., Zuhl, F. & Seemuller, E. The proteasome: paradigm of a self-compartmentalizing protease. Cell 92, 367–380 (1998).

    Article  CAS  Google Scholar 

  20. Tanaka, K. & Kasahara, M. The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-γ-inducible proteasome activator PA28. Immunol. Rev. 163, 161–176 (1998).

    Article  CAS  Google Scholar 

  21. Preckel, T. et al. Impaired immunoproteasome assembly and immune responses in PA28-/- mice. Science 286, 2162–2165 (1999).

    Article  CAS  Google Scholar 

  22. Tanahashi, N. et al. Hybrid proteasomes. Induction by interferon-γ and contribution to ATP-dependent proteolysis. J. Biol. Chem. 275, 14336–14345 (2000).

    Article  CAS  Google Scholar 

  23. Firestein, G. S. & Zvaifler, N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 33, 768–773 (1990).

    Article  CAS  Google Scholar 

  24. Kinne, R. W., Palombo-Kinne, E. & Emmrich, F. T-cells in the pathogenesis of rheumatoid arthritis: villains or accomplices? Biochim. Biophys. Acta 1360, 109–141 (1997).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. Gravallese, E. M. et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum. 43, 250–258 (2000).

    Article  CAS  Google Scholar 

  27. Billiau, A. Interferon-γ: biology and role in pathogenesis. Adv. Immunol. 62, 61–130 (1996).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  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).

    Article  CAS  Google Scholar 

  30. 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, 3597–3602 (1998).

    Article  ADS  CAS  Google Scholar 

Download references


We thank J. Inoue for the gift of TRAF6 cDNA; T. Kitamura for the pMX vectors; E. Barsoumian for critical reading of the manuscript; I. Kawai for assistance; and M. Asagiri for discussion. This work was supported by a grant for Advanced Research on Cancer from the Ministry of Education, Science, Sports and Culture 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; and a grant from Japan Orthopaedics and Traumatology Foundation.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Tadatsugu Taniguchi.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing