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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Tadatsugu Taniguchi.

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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). https://doi.org/10.1038/35046102

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