Role of the A20-TRAF6 axis in lipopolysaccharide-mediated osteoclastogenesis.
Bacterial lipopolysaccharide (LPS) has long been suggested as a potent inducer of bone loss in vivo despite controversial effects on osteoclast precursors. Recently, the role of the deubiquitinating protease A20 in regulating the LPS response in various organs was reported. In the present study, we investigated whether A20 is expressed in osteoclast cultures in response to RANKL or LPS and whether this protein plays a role in osteoclast formation and activation. Human peripheral blood mononuclear cells were cultured in the presence of M-CSF ± RANKL ± LPS. Although LPS induced the formation of multinucleated TRAP-positive cells expressing OSCAR, cathepsin K, and the calcitonin receptor, these cells were not capable of lacunar resorption. Release of TNF-α was noted in LPS-treated cultures, and the addition of a neutralizing anti-TNF-α antibody abrogated osteoclast formation in these cultures. A20 appeared to be a late-expressed gene in LPS-treated cultures and was associated with TRAF6 degradation and NF-κB inhibition. Silencing of A20 restored TRAF6 expression and NF-κB activation and resulted in increased bone resorption in LPS-treated cultures. A20 appeared important in the control of bone resorption and could represent a therapeutic target to treat patients with bone resorption associated with inflammatory diseases.
Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, OX3 7LD Oxford, United Kingdom. guillaume.mabilleau@univ-angers.fr
Guillaume
G
Mabilleau
Daniel
D
Chappard
Afsie
A
Sabokbar
D001862:Bone Resorption / Q000209:etiology* / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009687:Nuclear Proteins; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3