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Here, we explored the efficacy of the potent TGF\u2010\u03b2\u2010activated kinase\u20101 (TAK1) inhibitor LL\u2010Z1640\u20102 (LLZ) on joint inflammation and bone destruction in collagen\u2010induced arthritis (CIA).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>LL\u2010Z1640\u20102 was administered every other day in CIA mice. Clinical and histological evaluation was performed. Priming and activation of NLRP3 inflammasome and osteoclastogenic activity were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>NLRP3 inflammasome formation was observed in synovial macrophages and osteoclasts (OCs) in CIA mice. TACE and RANKL were also overexpressed in synovial macrophages and fibroblasts, respectively, in the CIA joints. Treatment with LLZ mitigated all the above changes. As a result, LLZ markedly suppressed synovial hypertrophy and pannus formation to alleviate pain and inflammation in CIA mice. LLZ could block the priming and activation of NLRP3 inflammasome in RAW264.7 macrophage cell line, primary bone marrow macrophages and OCs upon treatment with LPS followed by ATP, thereby suppressing their IL\u20101\u03b2 production. LLZ also suppressed LPS\u2010induced production of TACE and TNF\u2010\u03b1 in bone marrow macrophages and abolished IL\u20101\u03b2\u2010induced production of MMP\u20103, IL\u20106 and RANKL in synovial fibroblasts. In addition, LLZ directly inhibits RANKL\u2010mediated OC formation and activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TAK1 inhibition with LLZ may become a novel treatment strategy to effectively alleviate inflammasome\u2010mediated inflammation and RANKL\u2010induced osteoclastic bone destruction in joints alongside its potent suppression of TNF\u2010\u03b1 and IL\u20106 production and proteinase\u2010mediated pathological processes in RA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cti2.1371","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T06:19:51Z","timestamp":1642659591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["TGF\u2010\u03b2\u2010activated kinase\u20101 inhibitor LL\u2010Z1640\u20102 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF\u2010\u03b1 and RANKL expression"],"prefix":"10.1002","volume":"11","author":[{"given":"Hirofumi","family":"Tenshin","sequence":"first","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"},{"name":"Department of Hematology, Endocrinology and Metabolism Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jumpei","family":"Teramachi","sequence":"additional","affiliation":[{"name":"Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama University  Okayama Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohannad","family":"Ashtar","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics Tokushima University Graduate School of Biomedical Sciences  Tokushima 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