{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:49:08Z","timestamp":1791866948649,"version":"4.3.4"},"reference-count":41,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["1257523N"],"award-info":[{"award-number":["1257523N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["G0A5124N"],"award-info":[{"award-number":["G0A5124N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003130","name":"Fonds Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["11A2721N"],"award-info":[{"award-number":["11A2721N"]}],"id":[{"id":"10.13039\/501100003130","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Glucocorticoids remain essential therapies for immune and inflammatory diseases such as rheumatoid arthritis (RA) but are notorious for their metabolic side effects. Given the anti\u2010inflammatory and metabolically favorable actions of peroxisome proliferator\u2013activated nuclear receptor (PPAR) agonists, we investigated whether PPAR\u03b1 agonism could enhance the therapeutic efficacy and\/or mitigate the metabolic side effects of glucocorticoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the effects of the synthetic glucocorticoid dexamethasone and the PPAR\u03b1 agonist GW7647 across four model systems: tumor necrosis factor\u2010\u03b1 (TNF\u03b1)\u2013stimulated L929sA fibroblasts, primary human fibroblast\u2010like synoviocytes (FLS) from patients with osteoarthritis (OA) and RA, and collagen\u2010induced arthritis mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Dexamethasone reduced the inflammatory TNF\u03b1 response in L929sA cells, which was further potentiated by GW7647. In vivo, dexamethasone induced adiposity and hypertriglyceridemia, which GW7647 counteracted without affecting arthritis severity. In both OA\u2010FLS and RA\u2010FLS, dexamethasone and GW7647 cooperatively regulated metabolic genes expression. Proteomic profiling of TNF\u03b1\u2010stimulated human OA\u2010FLS revealed that combined use of dexamethasone and GW suppressed interferon\u2010stimulated proteins. In line herewith, suppression of proinflammatory gene expression upon combined dexamethasone and GW7647 treatment was more outspoken in L929sA co\u2010stimulated with TNF\u03b1 and interferon\u2010\u03b2 compared to TNF\u03b1 alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>GW enhances the anti\u2010inflammatory effects of glucocorticoids in L929sA cells and mitigates metabolic side effects of dexamethasone in vivo, without compromising efficacy. In human OA\u2010FLS and RA\u2010FLS, this combination cooperatively regulates metabolic gene expression. Moreover, PPAR\u03b1 agonism permits to broaden its anti\u2010inflammatory profile to interferon\u2010driven pathways. Because both glucocorticoids and PPAR agonists are already widely used in clinical practice, these findings offer a promising strategy to optimize glucocorticoid\u2010based therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70331","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:25:32Z","timestamp":1788773132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing Efficacy to Safety Ratio of Glucocorticoids in Rheumatoid Arthritis Models by Leveraging Peroxisome Proliferator\u2013Activated Nuclear Receptor\u2010\u03b1 Agonism"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1130-227X","authenticated-orcid":false,"given":"Lisa L.","family":"Koorneef","sequence":"first","affiliation":[{"name":"Vlaams Instituut voor Biotechnologie (VIB) Center for Medical Biotechnology  Ghent Belgium"},{"name":"Department of Biomolecular 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