DNA damage drives accelerated bone aging via an NF‐κB–dependent mechanism. (17th April 2013)

• Record Type: Journal Article
• Authors: Chen, Qian; Liu, Kai; Robinson, Andria R; Clauson, Cheryl L; Blair, Harry C; Robbins, Paul D; Niedernhofer, Laura J; Ouyang, Hongjiao
• Is Part Of: Journal of bone and mineral research. Volume 28:Number 5(2013:May)
• Page Start: 1214
• Page End: 1228
• Publication Date: 2013-04-17
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.1851
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <italic>Ercc1</italic>‐null (<italic>Ercc1</italic><sup>−/−</sup>) and hypomorphic (<italic>Ercc1</italic><sup>−/Δ</sup>) mice, to investigate the mechanism by which DNA damage leads to accelerated bone aging. Compared to their wild‐type littermates, both <italic>Ercc1</italic><sup>−/−</sup> and <italic>Ercc1</italic><sup>−/Δ</sup> 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 <italic>Ercc1</italic> mutant mice. Importantly, we demonstrated that haploinsufficiency of the p65 NF‐κB subunit partially rescued the osteoporosis phenotype of <italic>Ercc1</italic><sup>−/Δ</sup> mice. Finally, pharmacological inhibition of the NF‐κB signaling via an I‐κB kinase (IKK) inhibitor reversed cellular senescence and SASP in <italic>Ercc1</italic><sup>−/Δ</sup> 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. © 2013 American Society for Bone and Mineral Research.</p> </abstract>