Nishikawa Masataka, Myoui Akira, Tomita Tetsuya, Takahi Koichiro, Nampei Akihide, Yoshikawa Hideki
Osaka University Graduate School of Medicine, Osaka, Japan.
Arthritis Rheum. 2003 Sep;48(9):2670-81. doi: 10.1002/art.11227.
FR167653 is a potent inhibitor of p38 mitogen-activated protein kinase (MAPK) and inhibits tumor necrosis factor alpha (TNFalpha) and interleukin-1 beta (IL-1 beta) production in inflammatory cells. In this study we investigated the effect of FR167653 on collagen-induced arthritis (CIA).
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 kappa B ligand (sRANKL) and TNFalpha was examined.
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-1 beta, lowered the IL-1 beta 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.
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.
FR167653是一种有效的p38丝裂原活化蛋白激酶（MAPK）抑制剂，可抑制炎性细胞中肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）的产生。在本研究中，我们调查了FR167653对胶原诱导的关节炎（CIA）的影响。
预防性治疗组在加强注射当天（第7天）开始皮下注射FR167653（32mg/kg/天），治疗性治疗组在关节炎发作后（第21天）开始注射。评估后爪肿胀、体重、影像学和组织学评分以及破骨细胞数量。通过酶联免疫吸附测定评估血清和组织中的细胞因子水平。对来自骨髓的T淋巴细胞进行流式细胞术分析。检测FR167653对核因子κB受体活化因子配体（sRANKL）和TNFα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，但在预防性治疗组中不明显。治疗性治疗也显著减轻了爪肿胀。治疗组的平均影像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。FR167653治疗降低了TNFα和IL-1β的血清水平，降低了踝关节中IL-1β的浓度，并减少了骨髓中CD4+、CD8a+ T细胞群体。此外，FR167653在体外抑制了sRANKL和TNFα诱导的破骨细胞样细胞分化。
FR167653在预防性治疗模型中可预防关节炎的发作，并在治疗性治疗模型中抑制关节破坏的进展，提示p38 MAPK是类风湿性关节炎的一个潜在治疗靶点。
