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

Hiroshi Takayanagi, Kouetsu Ogasawara, Shigeaki Hida, Tomoki Chiba, Shigeo Murata, Kojiro Sato, Akinori Takaoka, Taeko Yokochi, Hiromi Oda, Keiji Tanaka, Kozo Nakamura, Tadatsugu Taniguchi

Research output: Contribution to journalArticlepeer-review

1089 Citations (Scopus)


Bone resorption is regulated by the immune system, 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 arthritis. However, whether activated T cells maintain bone homeostasis by counter-balancing 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 over-expressing 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.

Original languageEnglish
Pages (from-to)600-605
Number of pages6
Issue number6812
Publication statusPublished - 2000 Nov 30
Externally publishedYes

ASJC Scopus subject areas

  • General


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