title: Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation.
abstract: The cytokines RANKL and TNF activate NF-κB signaling in osteoclast precursors (OCPs) to induce osteoclast (OC) formation. Conversely, TNF can limit OC formation through NF-κB p100, which acts as an inhibitor, and TNF receptor-associated receptor 3 (TRAF3); however, a role for TRAF3 in RANKL-mediated OC formation is unknown. We found that TRAF3 limits RANKL-induced osteoclastogenesis by suppressing canonical and noncanonical NF-κB signaling. Conditional OC-specific Traf3-KO (cKO) mice had mild osteoporosis and increased OC formation. RANKL induced TRAF3 degradation via the lysosome/autophagy system. The autophagy/lysosome inhibitor chloroquine reduced RANKL-induced OC formation and function by increasing TRAF3 expression in OCPs in vitro and in vivo. Although chloroquine had no effect on basal bone resorption, it inhibited parathyroid hormone- and ovariectomy-induced OC activation in WT, but not cKO, mice. Deletion of the transcription factor gene Relb resulted in increased TRAF3 expression in OCPs, which was associated with decreased RANKL-induced TRAF3 degradation. RelB directly increased expression of BECN1, a key autophagy regulator, by binding to its promoter. These data indicate that autophagic/lysosomal degradation of TRAF3 is an important step in RANKL-induced NF-κB activation in OCPs. Furthermore, treatments that increase TRAF3 levels in OCPs, including pharmacological inhibition of its degradation with compounds such as chloroquine, may limit bone destruction in common bone diseases.
authors: Yan
authors: Y
authors: Xiu
authors: Hao
authors: H
authors: Xu
authors: Chen
authors: C
authors: Zhao
authors: Jinbo
authors: J
authors: Li
authors: Yoshikazu
authors: Y
authors: Morita
authors: Zhenqiang
authors: Z
authors: Yao
authors: Lianping
authors: L
authors: Xing
authors: Brendan F
authors: BF
authors: Boyce
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000071186:Beclin-1; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D008247:Lysosomes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D059748:Proteolysis; D053245:RANK Ligand / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3 / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D053245:RANK Ligand; C497594:Relb protein, mouse; D048008:TNF Receptor-Associated Factor 3; C505689:Tnfsf11 protein, mouse; D051841:Transcription Factor RelB; D002738:Chloroquine