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 and Tadatsugu Taniguchi ()
Additional contact information
Hiroshi Takayanagi: and
Kouetsu Ogasawara: and
Shigeaki Hida: and
Tomoki Chiba: Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Technology Corporation
Shigeo Murata: Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Technology Corporation
Kojiro Sato: and
Akinori Takaoka: and
Taeko Yokochi: and
Hiromi Oda: University of Tokyo
Keiji Tanaka: Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Technology Corporation
Kozo Nakamura: University of Tokyo
Tadatsugu Taniguchi: and

Nature, 2000, vol. 408, issue 6812, 600-605

Abstract: 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.

Date: 2000
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DOI: 10.1038/35046102

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