Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653
Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653
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DOI：
10.1002/art.11227
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Yoshikawa, H
中科院分区：
文献类型：
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作者：
Nishikawa, M;Myoui, A;Yoshikawa, H
Objective. FR 167653是p38丝裂原活化蛋白激酶（MAPK）的强效抑制剂，并抑制炎症细胞中肿瘤坏死因子α（TNF α）和白细胞介素-1 β（IL-1 β）的产生。在这项研究中，我们研究了FR 167653对胶原诱导的关节炎（CIA）的作用。在预防性治疗组中，从加强注射当天（第7天）开始，在治疗性治疗组中，在关节炎发作后（第21天），对患有CIA的大鼠皮下注射FR 167653（32 mg/kg/天）。评价后爪肿胀、体重、放射学和组织学评分以及破骨细胞数量。血清和组织中的细胞因子水平通过酶联免疫吸附试验进行了评估。对骨髓T淋巴细胞进行流式细胞术分析。检测FR 167653对可溶性核因子κ B受体激活剂配体（sRANKL）和TNF α诱导的体外破骨细胞形成的影响。CIA大鼠出现后爪肿胀和体重减轻，但预防性治疗组中这一点并不明显。治疗性处理也显著减少了爪肿胀。治疗组的平均放射学和组织学评分以及破骨细胞数量显著低于未治疗的CIA大鼠。FR 167653治疗降低了TNF α和IL-1 β的血清水平，降低了踝关节中的IL-1 β浓度，并降低了骨髓中的CD 4-、CD 8a + T细胞群。FR 167653对sRANKL和TNF α诱导的破骨细胞样细胞分化具有抑制作用。FR 167653在预防性治疗模型中预防关节炎的发作，并在治疗性治疗模型中抑制关节破坏的进展，表明p38 MAPK是类风湿性关节炎的潜在治疗靶点。
Objective. FR167653 is a potent inhibitor of p38 mitogen-activated protein kinase (MAPK) and inhibits tumor necrosis factor alpha (TNFalpha) and interleukin-1beta (IL-1beta) production in inflammatory cells. In this study we investigated the effect of FR167653 on collagen-induced arthritis (CIA).Methods. Rats with CIA were subcutaneously injected with FR167653 (32 mg/kg/day) starting on the day of the booster injection (day 7) in the prophylactic treatment group and after the onset of arthritis (day 21) in the therapeutic treatment group. Hind-paw swelling, body weight, radiographic and histologic scores, and osteoclast number were evaluated. Cytokine levels in the serum and tissue were assessed by enzyme-linked immunosorbent assays. Flow cytometric analysis of T lymphocytes from bone marrow was performed. The effect of FR167653 on in vitro osteoclast formation induced by soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and TNFalpha was examined.Results. Swelling of hind paws and loss of weight occurred in the CIA rats, but this was not evident in the prophylactic treatment group. Therapeutic treatment also significantly reduced paw swelling. The mean radiographic and histologic scores as well as the osteoclast numbers were significantly lower in the treatment group than in the CIA rats without treatment. FR167653 treatment reduced the serum levels of TNFalpha and IL-1beta, lowered the IL-1beta concentration in the ankle joints, and decreased the CD4-,CD8a+ T cell population in bone marrow. Furthermore, FR167653 inhibited the osteoclast-like cell differentiation induced by both sRANKL and TNFalpha in vitro.Conclusion. FR167653 prevents the onset of arthritis in a prophylactic treatment model and suppresses the progression of joint destruction in a therapeutic treatment model, suggesting that p38 MAPK is a potential therapeutic target for rheumatoid arthritis.