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Chloroquine reduces osteoclastogenesis in murine osteoporosis by preventing TRAF3 degradation
Open accessAbstract
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.
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“conditional deletion of TRAF3, an inhibitor of the noncanonical pathway, in osteoclast precursors resulted in increased osteoclast formation and bone resorption in mice.171”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [171]
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Metadata
- Authors
- Xiu, Y., Xu, H., Zhao, C., Li, J., Morita, Y., Yao, Z., Xing, L., & Boyce, B. F.
- Affiliations
- University of Rochester Medicine (US)
- Corresponding author
- Boyce, Brendan F.
- Venue
- Journal of Clinical Investigation
- Published
- 2013-12-09
- Volume
- 124
- Issue
- 1
- Pages
- 297-310
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3871219
- OpenAlex
- W2103768376
- Cited by
- 164
- References
- 72
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 7 · 2023: 12 · 2022: 14 · 2021: 16 · 2020: 26 · 2019: 20 · 2018: 13 · 2017: 20 · 2016: 6 · 2015: 7 · 2014: 4
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Rochester
- Medical Center, University of Rochester
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR061307, T32AR053459, AR 43510, AR 48697, R01AR048697, R01AR063650, R01AR043510)
- National Center for Research Resources (S10RR027340)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- chloroquine, osteoclastogenesis, TRAF3, RANKL, NF-κB signaling, autophagy, lysosomal degradation, osteoporosis, RelB, Beclin-1, osteoclast precursors, bone resorption, ovariectomy, parathyroid hormone
- MeSH terms
- Beclin-1, Animals, Bone Resorption, Cells, Cultured, Chloroquine, Female, Gene Expression Regulation, Lysosomes, Mice, Inbred C57BL, Osteoclasts, Osteoporosis, Promoter Regions, Genetic, Protein Binding, Mice, Knockout, TNF Receptor-Associated Factor 3, Apoptosis Regulatory Proteins, Mice, Transcription Factor RelB, RANK Ligand, Proteolysis
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