Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice

Genes Cells. 1999 Jun;4(6):353-62. doi: 10.1046/j.1365-2443.1999.00265.x.


Background: TRAF6, a member of the tumour necrosis factor receptor-associated factor family, was first identified as a transducer of CD40 and interleukin-1 receptor (IL-1R) signals based on the interaction of TRAF6 with the cytoplasmic tail of CD40 and with the IL-1R associated kinase in vitro. However, the functions of TRAF6 in vivo remain unidentified.

Results: We show that TRAF6-/- mice exhibit severe osteopetrosis and are defective in osteoclast formation. In vitro culture experiments revealed that osteoclast precursor cells derived from TRAF6-/- mice are unable to differentiate to functional osteoclasts in response to osteoclast differentiation factor (ODF). In bone marrow of TRAF6-/- mice, the number of sIgM+B220+ immature B cells is markedly reduced while the ratio of proB to preB cells is not affected. In contrast, development of thymocytes is not affected. Furthermore, TRAF6-/- mice are defective in lymph node organogenesis and IL-1 signalling in thymocytes.

Conclusions: The results identify TRAF6 as an essential component of ODF signalling pathway, and also show that TRAF6 plays pivotal roles in immune and inflammatory systems in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Cell Differentiation
  • Embryonic and Fetal Development
  • Interleukin-1 / metabolism*
  • Lymph Nodes / embryology*
  • Mice
  • Mice, Knockout
  • Osteoclasts / cytology
  • Osteopetrosis / genetics*
  • Proteins / genetics*
  • Proteins / metabolism
  • Receptors, Tumor Necrosis Factor / metabolism
  • Signal Transduction / genetics*
  • Spleen / cytology
  • TNF Receptor-Associated Factor 6


  • Interleukin-1
  • Proteins
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 6