{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T06:30:08Z","timestamp":1791095408423,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,12,21]],"date-time":"2012-12-21T00:00:00Z","timestamp":1356048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats: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\u2013xeroderma 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\u2013deficient mice, including Ercc1-null (Ercc1\u2212\/\u2212) and hypomorphic (Ercc1\u2212\/\u0394) mice, to investigate the mechanism by which DNA damage leads to accelerated bone aging. Compared to their wild-type littermates, both Ercc1\u2212\/\u2212 and Ercc1\u2212\/\u0394 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 \u03b1 (TNF\u03b1), and receptor activator of NF-\u03baB ligand (RANKL), and thereby induces an inflammatory bone microenvironment favoring osteoclastogenesis. Furthermore, we found that the transcription factor NF-\u03baB is activated in osteoblastic and osteoclastic cells of the Ercc1 mutant mice. Importantly, we demonstrated that haploinsufficiency of the p65 NF-\u03baB subunit partially rescued the osteoporosis phenotype of Ercc1\u2212\/\u0394 mice. Finally, pharmacological inhibition of the NF-\u03baB signaling via an I-\u03baB kinase (IKK) inhibitor reversed cellular senescence and SASP in Ercc1\u2212\/\u0394 BMSCs. These results demonstrate that DNA damage drives osteoporosis through an NF-\u03baB\u2013dependent mechanism. Therefore, the NF-\u03baB pathway represents a novel therapeutic target to treat aging-related bone disease. \u00a9 2013 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1851","type":"journal-article","created":{"date-parts":[[2012,12,22]],"date-time":"2012-12-22T01:06:05Z","timestamp":1356138365000},"page":"1214-1228","source":"Crossref","is-referenced-by-count":126,"title":["DNA damage drives accelerated bone aging via an NF-\n                    <b>\u03ba<\/b>\n                    B\u2013dependent mechanism"],"prefix":"10.1093","volume":"28","author":[{"given":"Qian","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oral Biology, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andria R","family":"Robinson","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA"},{"name":"Department of Human Genetics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl L","family":"Clauson","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"name":"University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry C","family":"Blair","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"name":"Pittsburgh Veteran's Affairs Medical Center, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D","family":"Robbins","sequence":"additional","affiliation":[{"name":"7 Paul D Robbins and Laura J Niedernhofer, Department of Metabolism and Aging, Scripps Florida, Jupiter, FL 33458, USA."},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"name":"University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J","family":"Niedernhofer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"name":"University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjiao","family":"Ouyang","sequence":"additional","affiliation":[{"name":"McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"name":"Center for Craniofacial Regeneration, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA"},{"name":"Department of Restorative Dentistry and Comprehensive Care, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA"},{"name":"Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,12,21]]},"reference":[{"issue":"9773","key":"2024020318394233300_bib1","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/S0140-6736(10)62349-5","article-title":"Osteoporosis: now and the future","volume":"377","author":"Rachner","year":"2011","journal-title":"Lancet."},{"issue":"9","key":"2024020318394233300_bib2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/nrrheum.2010.106","article-title":"Genetic epidemiology of age-related osteoporosis and its 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