{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:46:41Z","timestamp":1791600401440,"version":"4.3.4"},"reference-count":80,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"676","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2022,12,21]]},"abstract":"<jats:p>\n                    More than 40% of individuals will develop osteoarthritis (OA) during their lifetime, yet there are currently no licensed disease-modifying treatments for this disabling condition. Common polymorphic variants in\n                    <jats:italic>ALDH1A2<\/jats:italic>\n                    , which encodes the key enzyme for synthesis of all-trans retinoic acid (atRA), are associated with severe hand OA. Here, we sought to elucidate the biological significance of this association. We first confirmed that\n                    <jats:italic>ALDH1A2<\/jats:italic>\n                    risk variants were associated with hand OA in the U.K. Biobank. Articular cartilage was acquired from 33 individuals with hand OA at the time of routine hand OA surgery. After stratification by genotype, RNA sequencing was performed. A reciprocal relationship between\n                    <jats:italic>ALDH1A2<\/jats:italic>\n                    mRNA and inflammatory genes was observed. Articular cartilage injury up-regulated similar inflammatory genes by a process that we have previously termed mechanoflammation, which we believe is a primary driver of OA. Cartilage injury was also associated with a concomitant drop in atRA-inducible genes, which were used as a surrogate measure of cellular atRA concentration. Both responses to injury were reversed using talarozole, a retinoic acid metabolism blocking agent (RAMBA). Suppression of mechanoflammation by talarozole was mediated by a peroxisome proliferator\u2013activated receptor gamma (PPAR\u03b3)\u2013dependent mechanism. Talarozole was able to suppress mechano-inflammatory genes in articular cartilage in vivo 6 hours after mouse knee joint destabilization and reduced cartilage degradation and osteophyte formation after 26 days. These data show that boosting atRA suppresses mechanoflammation in the articular cartilage in vitro and in vivo and identifies RAMBAs as potential disease-modifying drugs for OA.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abm4054","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T13:58:21Z","timestamp":1671631101000},"source":"Crossref","is-referenced-by-count":48,"title":["Variants in\n                    <i>ALDH1A2<\/i>\n                    reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9594-7085","authenticated-orcid":true,"given":"Linyi","family":"Zhu","sequence":"first","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pragash","family":"Kamalathevan","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9529-4886","authenticated-orcid":true,"given":"Lada A.","family":"Koneva","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4739-7389","authenticated-orcid":true,"given":"Jadwiga Miotla","family":"Zarebska","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasios","family":"Chanalaris","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Ismail","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."},{"name":"Healthy Lifespan Institute (HELSI) and Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield S10 2TN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4944-123X","authenticated-orcid":true,"given":"Akira","family":"Wiberg","sequence":"additional","affiliation":[{"name":"Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3463-5568","authenticated-orcid":true,"given":"Michael","family":"Ng","sequence":"additional","affiliation":[{"name":"Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayat","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1287-9580","authenticated-orcid":true,"given":"John","family":"Walsby-Tickle","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4733-1205","authenticated-orcid":true,"given":"James S.O.","family":"McCullagh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona E.","family":"Watt","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."},{"name":"Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The Oxford Hand Surgical Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4569-8513","authenticated-orcid":true,"given":"Stephen N.","family":"Sansom","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2780-7173","authenticated-orcid":true,"given":"Dominic","family":"Furniss","sequence":"additional","affiliation":[{"name":"Botnar Research Centre, Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7LD, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8058-4186","authenticated-orcid":true,"given":"Matthew D.","family":"Gardiner","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3412-5712","authenticated-orcid":true,"given":"Tonia L.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford OX3 7FY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204680"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34453"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2009.06.001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.44"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(20)30279-4"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2019.09.018"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38039"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.37765"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.39965"},{"key":"e_1_3_3_11_2","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1002\/art.39547","article-title":"Brief report: JNK-2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis","volume":"68","author":"Ismail H. M.","year":"2016","unstructured":"H. M.\u00a0Ismail, J.\u00a0Miotla-Zarebska, L.\u00a0Troeberg, X.\u00a0Tang, B.\u00a0Stott, K.\u00a0Yamamoto, H.\u00a0Nagase, A. J.\u00a0Fosang, T. L.\u00a0Vincent, J.\u00a0Saklatvala,Brief report: JNK-2 controls aggrecan degradation in murine articular cartilage and the development of experimental osteoarthritis. Arthritis Rheumatol.68,1165\u20131171 (2016).","journal-title":"Arthritis Rheumatol."},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.34420"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4324"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2009.125435"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2011.150078"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwf141"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2957"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.40545"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.151878"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R030833"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2005.05.005"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.361790"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134996"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.107400"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1210\/mend.14.9.0518"},{"key":"e_1_3_3_26_2","first-page":"2976","article-title":"RAR gamma 2 expression is regulated through a retinoic acid response element embedded in Sp1 sites","volume":"12","author":"Lehmann J. 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C.","year":"1998","unstructured":"T. C.\u00a0Roos, F. K.\u00a0Jugert, H. F.\u00a0Merk, D. R.\u00a0Bickers,Retinoid metabolism in the skin. Pharmacol. Rev.50,315\u2013333 (1998).","journal-title":"Pharmacol. 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