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

Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF-kappaB (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 s...

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Bibliographic Details
Published in:Journal of bone and mineral research 2010-06, Vol.25 (6), p.1282-1294
Main Authors: Otero, Jesse E, Dai, Simon, Alhawagri, Muhammad A, Darwech, Isra, Abu-Amer, Yousef
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Enzyme Activation
I-kappa B Kinase - metabolism
Intracellular Signaling Peptides and Proteins - metabolism
Mice
Mice, Knockout
Monocytes - cytology
NF-kappa B - metabolism
Osteoclasts - enzymology
Osteoclasts - pathology
Osteogenesis
Osteolysis - enzymology
Osteolysis - pathology
Phenotype
Protein Binding
RANK Ligand - metabolism
Receptor Activator of Nuclear Factor-kappa B - metabolism
Signal Transduction
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Summary:Monocytes differentiate into osteoclasts through stimulation of receptor activator of NF-kappaB (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 IKKbeta (IKKbeta(SSEE)) but not wild-type IKKbeta into monocytes stimulates differentiation of bona fide osteoclasts in the absence of RANK ligand (RANKL). This phenomenon is independent of upstream signals because IKKbeta(SSEE) induced the development of bone-resorbing osteoclasts from RANK and IKKalpha knockout monocytes and in conditions in which NEMO-IKKbeta association was inhibited. NF-kappaB p100 and p105, but not RelB, were critical mediators of this effect. Inflammatory autocrine signaling by tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) were dispensable for the spontaneous osteoclastogenesis driven by IKKbeta(SSEE). More important, adenoviral gene transfer of IKKbeta(SSEE) induced osteoclasts and osteolysis in calvariae and knees of mice. Our data establish the sufficiency of IKKbeta activation for osteolysis and suggest that IKKbeta hyperactivation may play a role in conditions of pathologic bone destruction refractory to RANK/RANKL proximal therapeutic interventions.
ISSN:1523-4681
DOI:10.1002/jbmr.4