{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T14:23:48Z","timestamp":1793975028273,"version":"4.8.0"},"reference-count":89,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"791","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,3,26]]},"abstract":"<jats:p>\n                    Osteoarthritis (OA) is a prevalent joint disease characterized by pain, disability, and loss of physical function, posing a challenge to public health. However, molecular mechanisms of OA pathogenesis have not been fully described. We report that tripartite motif containing 15 (TRIM15) is a regulator in chondrocyte senescence and OA. Our study revealed heightened expression of TRIM15 in chondrocytes of senescent cartilage from patients with OA and in aged wild-type mice. Using gain- and loss-of-function studies, we found that TRIM15 facilitated human chondrocyte senescence. Conditional deletion of\n                    <jats:italic>Trim15<\/jats:italic>\n                    in mouse chondrocytes severely impaired skeletal growth, partially because of impaired embryonic chondrocyte senescence. Compared with conditionally knocked out\n                    <jats:italic>\n                      Col2a1-CreER\n                      <jats:sup>T2<\/jats:sup>\n                      \/Trim15\n                      <jats:sup>flox\/flox<\/jats:sup>\n                    <\/jats:italic>\n                    mice,\n                    <jats:italic>Trim15<\/jats:italic>\n                    <jats:sup>flox\/flox<\/jats:sup>\n                    control mice exhibited accelerated OA phenotypes, increased senescence markers, and senescence-associated secretory phenotype during aging. Mechanistically, TRIM15 bound with yes-associated protein (YAP) and mediated K48-linked YAP ubiquitination at K254, which interrupted the interaction between YAP and angiomotin, leading to enhanced YAP nuclear translocation. Dysregulation of TRIM15-YAP and transcriptional coactivator with PDZ-binding motif (TAZ) signaling promoted OA progression in both the surgery-induced and natural aging\u2013induced mouse OA model. Intra-articular injection of adeno-associated virus 5 (AAV5)\u2013\n                    <jats:italic>Trim15<\/jats:italic>\n                    shRNA decelerated OA progression in mice. In particular, YAP and TAZ protein amounts were increased in chondrocytes of patients with OA. Our preclinical results demonstrated that the AAV5-\n                    <jats:italic>TRIM15<\/jats:italic>\n                    shRNA treatment protected human OA explants against degeneration through inhibiting chondrocyte senescence. Together, our findings underscore the potential of targeting TRIM15 in reshaping the aging cartilage microenvironment and suggest a promising therapeutic avenue for OA.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adq1735","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T14:15:38Z","timestamp":1742998538000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":26,"title":["TRIM15 drives chondrocyte senescence and osteoarthritis progression"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4272-9649","authenticated-orcid":true,"given":"Zhuang","family":"Li","sequence":"first","affiliation":[{"name":"Center of Joint and Sports Medicine, Orthopedics Department, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, 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