IKKβ activation is sufficient for RANK-independent osteoclast differentiation and osteolysis

Authors

  • Jesse E Otero,

    1. Departments of Orthopedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Simon Dai,

    1. Departments of Orthopedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Muhammad A Alhawagri,

    1. Departments of Orthopedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Isra Darwech,

    1. Departments of Orthopedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Yousef Abu-Amer

    Corresponding author
    1. Departments of Orthopedics and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    2. Orthopedic Research and Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA
    • Department of Orthopedic Research and Cell Biology & Physiology, Washington University School of medicine, 660 S. Euclid Avenue, Campus Box 8233, Saint Louis, MO 63110, USA.
    Search for more papers by this author

Abstract

Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF-κB (RANK). Many downstream effectors of RANK play a positive role in osteoclastogenesis, but their relative importance in osteoclast differentiation is unclear. We report the discovery that activation of a single pathway downstream of RANK is sufficient for osteoclast differentiation. In this regard, introduction of constitutively activated IKKβ (IKKβSSEE) but not wild-type IKKβ into monocytes stimulates differentiation of bona fide osteoclasts in the absence of RANK ligand (RANKL). This phenomenon is independent of upstream signals because IKKβSSEE induced the development of bone-resorbing osteoclasts from RANK and IKKα knockout monocytes and in conditions in which NEMO-IKKβ association was inhibited. NF-κB p100 and p105, but not RelB, were critical mediators of this effect. Inflammatory autocrine signaling by tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) were dispensable for the spontaneous osteoclastogenesis driven by IKKβSSEE. More important, adenoviral gene transfer of IKKβSSEE induced osteoclasts and osteolysis in calvariae and knees of mice. Our data establish the sufficiency of IKKβ activation for osteolysis and suggest that IKKβ hyperactivation may play a role in conditions of pathologic bone destruction refractory to RANK/RANKL proximal therapeutic interventions. © 2010 American Society for Bone and Mineral Research

Ancillary