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

Nature. 2000 Nov 30;408(6812):600-5. doi: 10.1038/35046102.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology
  • Autoantigens
  • Autoimmune Diseases / immunology
  • Bone Marrow Cells
  • Bone Resorption / immunology*
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Cysteine Endopeptidases / metabolism
  • Glycoproteins / physiology
  • Interferon-gamma / physiology*
  • JNK Mitogen-Activated Protein Kinases*
  • Lymphocyte Activation
  • MAP Kinase Kinase 4
  • Macrophages / cytology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Multienzyme Complexes / metabolism
  • NF-kappa B / metabolism
  • Osteoclasts / immunology
  • Osteoclasts / physiology*
  • Osteoprotegerin
  • Proteasome Endopeptidase Complex
  • Proteins / metabolism
  • Proteins / physiology
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Tumor Necrosis Factor
  • Signal Transduction*
  • T-Lymphocytes / physiology*
  • TNF Receptor-Associated Factor 6
  • Ubiquitins / metabolism


  • Autoantigens
  • Carrier Proteins
  • Glycoproteins
  • Ki antigen
  • Membrane Glycoproteins
  • Multienzyme Complexes
  • NF-kappa B
  • Osteoprotegerin
  • Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 6
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Ubiquitins
  • Interferon-gamma
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex