{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T17:55:20Z","timestamp":1781805320886,"version":"3.54.5"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172503"],"award-info":[{"award-number":["82172503"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1) is a key regulator of cellular adaptation to hypoxia, but its role in osteoarthritis (OA) remains incompletely defined. This study aimed to investigate the contribution of HIF-2\u03b1 to OA pathogenesis and the underlying molecular mechanisms. Human cartilage specimens were collected to examine HIF-2\u03b1 expression and components of the histone deacetylase 4 (HDAC4) signaling pathway using Western blotting, quantitative real-time PCR, and immunohistochemistry. An\n                    <jats:italic>in vitro<\/jats:italic>\n                    OA model was established in chondrocytes using interleukin-1\u03b2 (IL-1\u03b2), followed by HIF-2\u03b1 knockdown with small interfering RNA and overexpression via adenoviral transduction. Chondrocyte apoptosis was assessed by flow cytometry and TUNEL staining. To evaluate\n                    <jats:italic>in vivo<\/jats:italic>\n                    effects, HIF-2\u03b1 was silenced using an adeno-associated viral vector in a rat OA model induced by anterior cruciate ligament transection (ACLT). Disease progression was assessed by X-ray, computed tomography (CT), FMT\u00ae small animal\n                    <jats:italic>in vivo<\/jats:italic>\n                    fluorescence molecular tomography imaging system, Safranin O staining, and immunohistochemistry. HIF-2\u03b1 expression was significantly increased in cartilage from OA patients and ACLT rats.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , HIF-2\u03b1 modulation altered HDAC4 expression and downstream apoptotic signaling. Knockdown of HIF-2\u03b1 reduced chondrocyte apoptosis and attenuated cartilage degeneration\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These findings indicate that HIF-2\u03b1 promotes OA progression by regulating chondrocyte apoptosis and matrix homeostasis through the HDAC4-ATF4-CHOP pathway. This study identifies a previously unrecognized mechanism linking HIF-2\u03b1 to OA and highlights its potential as a therapeutic target.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0351847","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T17:26:35Z","timestamp":1781803595000},"page":"e0351847","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["HIF-2\u03b1 drives osteoarthritis progression via suppression of the HDAC4-ATF4-CHOP signaling 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