{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:02:23Z","timestamp":1790074943746,"version":"4.0.1"},"reference-count":0,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>SIRT6 is a nuclear\u2010localized histone deacetylase that regulates multiple pathways associated with aging. This study aimed to determine whether systemic administration of a small molecule activator of SIRT6, MDL\u2010800, decreases the severity of age\u2010associated osteoarthritis (OA) in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male 18\u2010month\u2010old mice received weekly intraperitoneal injections of MDL\u2010800 or vehicle control for 6 months, and OA severity was assessed at 24 months using histology, micro\u2010CT, and histomorphometry. The role of MDL\u2010800\u2010induced SIRT6 activation in human chondrocyte function was analyzed using RNA sequencing and immunoblotting. The effect of MDL\u2010800 to reduce DNA damage was assessed in human and mouse synovial fibroblasts by the comet assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mice receiving long\u2010term administration of MDL\u2010800 were protected from OA pathology when compared to controls, as characterized by less cartilage damage, osteophyte formation, synovial hyperplasia, subchondral bone sclerosis, and meniscal ossification. RNA sequencing of chondrocytes revealed that MDL\u2010800 negatively enriched pathways associated with bone formation, angiogenesis, and catabolic MAP kinase signaling, while positively enriching pathways associated with epigenetic regulation, telomere maintenance, mitochondrial function, redox balance, and DNA repair. MDL\u2010800 significantly decreased oxidative stress\u2010induced phosphorylation of p38 in chondrocytes and basal DNA damage in human and mouse synovial fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Activation of SIRT6 by MDL\u2010800 significantly protected old mice from age\u2010associated OA severity\n                      <jats:italic>in vivo<\/jats:italic>\n                      . MDL\u2010800 decreased pathways associated with pathological bone formation and regulated multiple hallmarks of aging. Targeted therapies that activate SIRT6 may represent a novel strategy to repress multiple aging pathways to slow, stop, or reverse age\u2010associated OA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70342","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:06:07Z","timestamp":1790071567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MDL\u2010800\u2010induced SIRT6 activation decreases age\u2010associated osteoarthritis in mice"],"prefix":"10.1002","author":[{"given":"Matheus Moreira","family":"Perez","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranay","family":"Ramteke","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahiyah","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen","family":"Haslam","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirene","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Chubinskaya","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Rush University Medical Center  Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy J.","family":"Peffers","sequence":"additional","affiliation":[{"name":"Institute of Life Course and Medical Sciences University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9690-6889","authenticated-orcid":false,"given":"William R.","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center University of North Carolina at Chapel Hill  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Shine","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center University of North Carolina at Chapel Hill  Chapel Hill NC USA"},{"name":"Lampe Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University  Raleigh NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9055-4282","authenticated-orcid":false,"given":"Brian O.","family":"Diekman","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center University of North Carolina at Chapel Hill  Chapel Hill NC USA"},{"name":"Lampe Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University  Raleigh NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2832-6144","authenticated-orcid":false,"given":"Richard F.","family":"Loeser","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center University of North Carolina at Chapel Hill  Chapel Hill NC USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa A.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makarand V.","family":"Risbud","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5743-3304","authenticated-orcid":false,"given":"John A.","family":"Collins","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Sidney Kimmel Medical College Thomas Jefferson University  Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,22]]},"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70342","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70342","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:06:07Z","timestamp":1790071567000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.70342"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,22]]},"references-count":0,"alternative-id":["10.1002\/art.70342"],"URL":"https:\/\/doi.org\/10.1002\/art.70342","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,22]]},"assertion":[{"value":"2026-04-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"art.70342"}}