TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling (original) (raw)

  1. Mark A. Lomaga,
  2. Wen-Chen Yeh,
  3. Ildiko Sarosi,
  4. Gordon S. Duncan,
  5. Caren Furlonger,
  6. Alexandra Ho,
  7. Sean Morony,
  8. Casey Capparelli,
  9. Gwyneth Van,
  10. Stephen Kaufman,
  11. Annette van der Heiden,
  12. Annick Itie,
  13. Andrew Wakeham,
  14. Wilson Khoo,
  15. Takehiko Sasaki,
  16. Zhaodan Cao,
  17. Josef M. Penninger,
  18. Christopher J. Paige,
  19. David L. Lacey,
  20. Colin R. Dunstan,
  21. William J. Boyle,
  22. David V. Goeddel, and
  23. Tak W. Mak
  24. Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 2S2; Amgen Institute, Ontario Cancer Institute and University of Toronto, Toronto, Ontario, Canada M5G 2C1; Amgen, Inc., Thousand Oaks, California 91320-1789 USA; Departments of Medical Biophysics and Immunology, University of Toronto and Ontario Cancer Institute, Toronto, Ontario, Canada M5G 2M9; Tularik, Inc., South San Francisco, California 94080 USA

Abstract

Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.

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