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T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma | | H Takayanagi
; K Ogasawara
; S Hida
; T Chiba
; S Murata
; K Sato
; A Takaoka
; T Yokochi
; H Oda
; K Tanaka
; K Nakamura
; T Taniguchi
; | | Date: |
30 Nov 2000 | | Journal: | Nature, 408 (6812), 600-5 | | Abstract: | Bone resorption is regulated by the immune system, where T-cell expression of RANKL (receptor activator of nuclear factor (NF)-kappaB 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 counterbalancing the action of RANKL remains unknown. Here we show that T-cell production of interferon (IFN)-gamma strongly suppresses osteoclastogenesis by interfering with the RANKL-RANK signalling pathway. IFN-gamma 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-kappaB 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-gamma action. Furthermore, we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFN-gamma-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-gamma 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. | | Source: | PubMed, pmid11117749 doi: 10.1038/35046102 | | Services: | Forum | Review | Favorites | |
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