PMID- 24316970
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20220316
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 124
IP  - 1
DP  - 2014 Jan
TI  - Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 
      degradation.
PG  - 297-310
LID - 66947 [pii]
LID - 10.1172/JCI66947 [doi]
AB  - The cytokines RANKL and TNF activate NF-kappaB signaling in osteoclast precursors 
      (OCPs) to induce osteoclast (OC) formation. Conversely, TNF can limit OC 
      formation through NF-kappaB 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-kappaB 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-kappaB 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.
FAU - Xiu, Yan
AU  - Xiu Y
FAU - Xu, Hao
AU  - Xu H
FAU - Zhao, Chen
AU  - Zhao C
FAU - Li, Jinbo
AU  - Li J
FAU - Morita, Yoshikazu
AU  - Morita Y
FAU - Yao, Zhenqiang
AU  - Yao Z
FAU - Xing, Lianping
AU  - Xing L
FAU - Boyce, Brendan F
AU  - Boyce BF
LA  - eng
GR  - R01 AR063650/AR/NIAMS NIH HHS/United States
GR  - T32 AR053459/AR/NIAMS NIH HHS/United States
GR  - 1S10RR027340/RR/NCRR NIH HHS/United States
GR  - P30 AR061307/AR/NIAMS NIH HHS/United States
GR  - T32AR053459/AR/NIAMS NIH HHS/United States
GR  - R01 AR048697/AR/NIAMS NIH HHS/United States
GR  - AR48697/AR/NIAMS NIH HHS/United States
GR  - P30AR061307/AR/NIAMS NIH HHS/United States
GR  - AR43510/AR/NIAMS NIH HHS/United States
GR  - R01 AR043510/AR/NIAMS NIH HHS/United States
GR  - S10 RR027340/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131209
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Beclin-1)
RN  - 0 (Becn1 protein, mouse)
RN  - 0 (RANK Ligand)
RN  - 0 (Relb protein, mouse)
RN  - 0 (TNF Receptor-Associated Factor 3)
RN  - 0 (Tnfsf11 protein, mouse)
RN  - 147337-75-5 (Transcription Factor RelB)
RN  - 886U3H6UFF (Chloroquine)
SB  - IM
MH  - Animals
MH  - Apoptosis Regulatory Proteins/genetics/metabolism
MH  - Beclin-1
MH  - Bone Resorption/drug therapy/metabolism
MH  - Cells, Cultured
MH  - Chloroquine/*pharmacology/therapeutic use
MH  - Female
MH  - Gene Expression Regulation
MH  - Lysosomes/drug effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Osteoclasts/drug effects/*physiology
MH  - Osteoporosis/*drug therapy/metabolism/pathology
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - Proteolysis
MH  - RANK Ligand/metabolism
MH  - TNF Receptor-Associated Factor 3/*metabolism
MH  - Transcription Factor RelB/genetics/metabolism
PMC - PMC3871219
EDAT- 2013/12/10 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/12/09
CRDT- 2013/12/10 06:00
PHST- 2013/08/19 00:00 [received]
PHST- 2013/10/03 00:00 [accepted]
PHST- 2013/12/10 06:00 [entrez]
PHST- 2013/12/10 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/12/09 00:00 [pmc-release]
AID - 66947 [pii]
AID - 10.1172/JCI66947 [doi]
PST - ppublish
SO  - J Clin Invest. 2014 Jan;124(1):297-310. doi: 10.1172/JCI66947. Epub 2013 Dec 9.