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 < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), 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 (p < 0.004) and cartilage damage (p < 0.004) 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 (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

中文翻译：

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用选择性抑制剂takinib抑制TAK1的药理作用可减轻CIA小鼠关节炎的临床表现

要检查塔基尼（一种选择性转化生长因子β激活的激酶1（TAK1）抑制剂）降低鼠II型胶原诱导的关节炎（CIA）严重程度并影响滑膜细胞功能的能力。CIA诱导后，每天用takinib（50 mg / kg）治疗小鼠，并评估临床评分。CIA诱导后三十六天，在经过处理和经媒介物处理的动物的各个关节上进行组织学检查。量化炎症，血管nu，软骨损伤，骨吸收和骨膜骨形成。此外，通过LC-MS在各种组织中评价了他基尼的药代动力学。用10μMtakinib培养类风湿关节炎成纤维样滑膜细胞（RA-FLS），并通过细胞因子/趋化因子蛋白质组芯片分析细胞因子的分泌。在有或没有肿瘤坏死因子（TNF）的情况下，使用24至48小时的培养物来测量takinib对RA-FLS的细胞毒性。在这里，我们显示了takinib在CIA类风湿性关节炎（RA）小鼠模型中降低临床评分的能力（p <0.001）。与媒介物治疗组相比，TAK1抑制作用减少了治疗组小鼠所有关节的炎症（p <0.01），软骨损伤（p <0.01），血管nu，骨吸收，骨膜骨形成和骨膜骨宽度。在患病的动物的膝盖上观察到炎症的明显减轻（p <0.004）和软骨损伤（p <0.004），在前爪和后爪中有中等程度的减轻。此外，他基尼的药代动力学显示血浆清除迅速（t1 / 2 = 21分钟）。takinib在刺激的RA-FLS细胞中降低了GROα，G-CSF，和ICAM-1促炎细胞因子信号转导。我们的发现支持以下假设：TAK1靶向疗法代表了一种新的治疗轴来治疗RA和其他炎症性疾病。