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Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10\u2009\u03bcM takinib and cytokine secretion analyzed by cytokine\/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48\u2009h cultures in the presence or absence of tumor necrosis factor (TNF).<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Here, we show takinib\u2019s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). TAK1 inhibition reduced inflammation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), cartilage damage (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.004) and cartilage damage (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t<jats:sub>\u00bd<\/jats:sub>\u2009=\u200921 min). In stimulated RA-FLS cells, takinib reduced GRO\u03b1, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13075-019-2073-x","type":"journal-article","created":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T19:03:02Z","timestamp":1576609382000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice"],"prefix":"10.1186","volume":"21","author":[{"given":"Scott A.","family":"Scarneo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liesl S.","family":"Eibschutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip J.","family":"Bendele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly W.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Totzke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A. 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TAH and PH are both part owners of EydisBio (Durham NC). Additionally, a patent has been issued (US10,207,998) for takinib, filed by TAH and PH. All other authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"292"}}