Document Detail


DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism.
MedLine Citation:
PMID:  23281008     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Advanced age is one of the most important risk factors for osteoporosis. Accumulation of oxidative DNA damage has been proposed to contribute to age-related deregulation of osteoblastic and osteoclastic cells. Excision repair cross complementary group 1-xeroderma pigmentosum group F (ERCC1-XPF) is an evolutionarily conserved structure-specific endonuclease that is required for multiple DNA repair pathways. Inherited mutations affecting expression of ERCC1-XPF cause a severe progeroid syndrome in humans, including early onset of osteopenia and osteoporosis, or anomalies in skeletal development. Herein, we used progeroid ERCC1-XPF-deficient mice, including Ercc1-null (Ercc1(-/-)) and hypomorphic (Ercc1(-/Δ)) mice, to investigate the mechanism by which DNA damage leads to accelerated bone aging. Compared to their wild-type littermates, both Ercc1(-/-) and Ercc1(-/Δ) mice display severe, progressive osteoporosis caused by reduced bone formation and enhanced osteoclastogenesis. ERCC1 deficiency leads to atrophy of osteoblastic progenitors in the bone marrow stromal cell (BMSC) population. There is increased cellular senescence of BMSCs and osteoblastic cells, as characterized by reduced proliferation, accumulation of DNA damage, and a senescence-associated secretory phenotype (SASP). This leads to enhanced secretion of inflammatory cytokines known to drive osteoclastogenesis, such as interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and receptor activator of NF-κB ligand (RANKL), and thereby induces an inflammatory bone microenvironment favoring osteoclastogenesis. Furthermore, we found that the transcription factor NF-κB is activated in osteoblastic and osteoclastic cells of the Ercc1 mutant mice. Importantly, we demonstrated that haploinsufficiency of the p65 NF-κB subunit partially rescued the osteoporosis phenotype of Ercc1(-/Δ) mice. Finally, pharmacological inhibition of the NF-κB signaling via an I-κB kinase (IKK) inhibitor reversed cellular senescence and SASP in Ercc1(-/Δ) BMSCs. These results demonstrate that DNA damage drives osteoporosis through an NF-κB-dependent mechanism. Therefore, the NF-κB pathway represents a novel therapeutic target to treat aging-related bone disease.
Authors:
Qian Chen; Kai Liu; Andria R Robinson; Cheryl L Clauson; Harry C Blair; Paul D Robbins; Laura J Niedernhofer; Hongjiao Ouyang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-18     Completed Date:  2013-10-18     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1214-28     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone and Bones / physiology*
Cell Differentiation
Cells, Cultured
DNA Damage*
DNA-Binding Proteins / genetics
Endonucleases / genetics
Mice
Mice, Knockout
NF-kappa B / metabolism*
Osteoblasts / pathology
Osteoporosis / genetics
Grant Support
ID/Acronym/Agency:
AG024827/AG/NIA NIH HHS; AG033907/AG/NIA NIH HHS; AR051456/AR/NIAMS NIH HHS; ES016114/ES/NIEHS NIH HHS; NS058451/NS/NINDS NIH HHS; P30 AG024827/AG/NIA NIH HHS; P30AG024827/AG/NIA NIH HHS; P30CA047904/CA/NCI NIH HHS; R01 ES016114/ES/NIEHS NIH HHS; R01AR055208/AR/NIAMS NIH HHS; R01DE017439/DE/NIDCR NIH HHS; R21CA161150/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/NF-kappa B; EC 3.1.-/Endonucleases; EC 3.1.-/Ercc1 protein, mouse
Comments/Corrections

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