{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:09:18Z","timestamp":1791641358376,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,10,27]],"date-time":"2018-10-27T00:00:00Z","timestamp":1540598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2018,12]]},"abstract":"Objective<\/jats:title>To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA<\/jats:styled-content>).<\/jats:p><\/jats:sec>Methods<\/jats:title>Ex vivo RA<\/jats:styled-content> synovial explants and primary RA<\/jats:styled-content> synovial fibroblasts (RASF<\/jats:styled-content>s) were cultured with 1 \u03bcM<\/jats:italic> tofacitinib. RASF<\/jats:styled-content> bioenergetics were assessed using an XF<\/jats:styled-content>24 analyzer, and key metabolic genes were assessed by reverse transcription\u2013polymerase chain reaction (RT<\/jats:styled-content>\u2010PCR<\/jats:styled-content>) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme\u2010linked immunosorbent assay (ELISA<\/jats:styled-content>). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA<\/jats:styled-content> whole tissue synovial explants was quantified by ELISA<\/jats:styled-content>s\/MSD<\/jats:styled-content> multiplex assays, and metabolic markers were quantified by RT<\/jats:styled-content>\u2010PCR<\/jats:styled-content>. Finally, RASF<\/jats:styled-content> invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion\/Matrigel outgrowth assays and ELISA<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASF<\/jats:styled-content>s and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP<\/jats:styled-content> production, and the maximal respiratory capacity and the respiratory reserve in RASF<\/jats:styled-content>s, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK<\/jats:styled-content>2), glycogen synthase kinase 3\u03b1 (GSK<\/jats:styled-content>\u20103\u03b1), lactate dehydrogenase A, and hypoxia\u2010inducible factor 1\u03b1. Tofacitinib inhibited the effect of oncostatin M (OSM<\/jats:styled-content>) on interleukin\u20106 (IL<\/jats:styled-content>\u20106) and monocyte chemotactic protein 1 and reversed the effects of OSM<\/jats:styled-content> on RASF<\/jats:styled-content> cellular metabolism. Using RA<\/jats:styled-content> whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6\u2010phosphofructo\u20102\u2010kinase\/fructose\u20102,6\u2010biphosphatase 3, 3\u2032\u2010phosphoinositide\u2013dependent protein kinase 1, HK<\/jats:styled-content>2, and GSK<\/jats:styled-content>\u20103\u03b1, the proinflammatory mediators IL<\/jats:styled-content>\u20106, IL<\/jats:styled-content>\u20108, IL<\/jats:styled-content>\u20101\u03b2, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE<\/jats:styled-content>\u20102, and RASF<\/jats:styled-content> outgrowth from synovial explants, RASF<\/jats:styled-content> invasion, and matrix metalloproteinase 1 activity.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>This study demonstrates that JAK<\/jats:styled-content>\/STAT<\/jats:styled-content> signaling mediates the complex interplay between inflammation and cellular metabolism in RA<\/jats:styled-content> pathogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40569","type":"journal-article","created":{"date-parts":[[2018,5,23]],"date-time":"2018-05-23T03:21:19Z","timestamp":1527045679000},"page":"1959-1970","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["JAK<\/scp>\/STAT<\/scp> Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"70","author":[{"given":"Trudy","family":"McGarry","sequence":"first","affiliation":[{"name":"Trinity College Dublin and St. Vincent's University Hospital University College Dublin Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Orr","sequence":"additional","affiliation":[{"name":"St. Vincent's University Hospital University College Dublin Dublin 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