Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice

• Published in: Arthritis research & therapy 2019-12, Vol.21 (1), p.292-292, Article 292
• Main Authors: Scarneo, Scott A, Eibschutz, Liesl S, Bendele, Phillip J, Yang, Kelly W, Totzke, Juliane, Hughes, Philip, Fox, David A, Haystead, Timothy A J
• Format: Article
• Language: English
• Subjects: Arthritis; B cells; Collagen; Cytokines; Disease; Edema; Inflammation; Inflammatory arthritis; Kinases; Knee; Laboratory animals; Pathogenesis; Proteins; Rheumatoid arthritis; Rheumatoid factor; Small molecule inhibitor; TAK1; Therapeutics; Tumor necrosis factor-TNF
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-019-2073-x

To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. 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 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p