{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:00:13Z","timestamp":1790928013833,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The precise role of hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1) in osteoarthritis (OA) pathogenesis remains controversial, often debated between a protective compensatory factor and a disease mediator. Here, we demonstrate that sustained, uncoupled HIF\u20101\u03b1 accumulation functions as a potent, compartment\u2010specific pathogenic driver of joint destruction. Using genetically engineered mouse models, we reveal that chondrocyte\u2010specific HIF\u20101\u03b1 overexpression (\n                    <jats:italic>Acan<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>CreERT2<\/jats:italic>\n                    <\/jats:sup>\n                    ;\n                    <jats:italic>Hif1\u03b1dPA<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>fl\/fl<\/jats:italic>\n                    <\/jats:sup>\n                    ) triggers spontaneous OA and exacerbates destabilization of the medial meniscus (DMM)\u2010induced post\u2010traumatic joint degeneration. Mechanistically, continuous HIF\u20101\u03b1 activation drives pathological angiogenesis that physically dismantles the avascular, hypoxic cartilage niche, forcing a profound metabolic dysregulation that culminates in catastrophic matrix degradation. Conversely, sustained HIF\u20101\u03b1 activation within the synovial and superficial cartilage compartments (\n                    <jats:italic>Prg4\u2010 GFPCreERT2<\/jats:italic>\n                    ;\n                    <jats:italic>Hif1\u03b1dPA<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>fl\/fl<\/jats:italic>\n                    <\/jats:sup>\n                    ) drives a slowly progressive, late\u2010onset spontaneous OA through chronic inflammatory accumulation that actively suppresses Col2a1 expression. Furthermore, this robust inflammatory priming establishes a highly vulnerable microenvironment, whereby DMM surgery significantly accelerates the progression of trauma\u2010induced joint collapse. Finally, transient whole\u2010joint HIF\u20101\u03b1 induction via an intra\u2010articular injection of lipid nanoparticles (LNP\u2010mRNA) closely recapitulates these detrimental effects. Collectively, our study reconciles existing controversies by establishing sustained HIF\u20101\u03b1 accumulation as a spatiotemporally dynamic, broad disease amplifier across the articular ecosystem, highlighting its targeted inhibition as a promising therapeutic strategy for OA.\n                  <\/jats:p>","DOI":"10.1111\/acel.70606","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:29:24Z","timestamp":1782271764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Sustained Hypoxia\u2010Inducible Factor 1\u2010Alpha Accumulation Disrupts the Articular Niche to Promote Osteoarthritis Pathogenesis"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2667-6973","authenticated-orcid":false,"given":"Weiyuan","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering The Hong Kong Polytechnic University  Hong Kong China"},{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6069-880X","authenticated-orcid":false,"given":"Chu","family":"Tao","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery The Seventh Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-6519","authenticated-orcid":false,"given":"Rongdong","family":"Liao","sequence":"additional","affiliation":[{"name":"Sichuan Provincial People's Hospital Sichuan Academy of Medical Sciences  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianglong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen China"},{"name":"Department of Joint and Orthopedics Zhujiang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiongtian","family":"Guo","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery The Seventh Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjue","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuxin","family":"Wei","sequence":"additional","affiliation":[{"name":"Shenzhen Key Laboratory of Bone Tissue Repair and Translational Research, Department of Orthopaedic Surgery The Seventh Affiliated Hospital of Sun Yat\u2010Sen University  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine Southern University of Science and Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4077-1198","authenticated-orcid":false,"given":"Lijun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Joint and Orthopedics Zhujiang Hospital, Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Chen","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences Shenzhen Institute of Advanced Technology  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment Southern University of Science and Technology  Shenzhen 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H.Welfley P.Brahmachary et\u00a0al.2024.\u201cMetabolomic Profiles and Pathways in Osteoarthritic Human Cartilage: A Comparative Analysis With Healthy Cartilage.\u201dbioRxiv: The Preprint Server for Biology.https:\/\/doi.org\/10.1101\/2024.01.25.577269.","DOI":"10.1101\/2024.01.25.577269"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2014.06.031"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43587\u2010021\u201000165\u2010w"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2021.08.005"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2026.101113"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jot.2023.05.005"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001330\u2010w"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202303261"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70606","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70606","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70606","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T04:57:36Z","timestamp":1784609856000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":45,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/acel.70606"],"URL":"https:\/\/doi.org\/10.1111\/acel.70606","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]},"assertion":[{"value":"2026-04-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70606"}}