Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice
Targeted mast cell silencing protects against joint destruction and angiogenesis in experimental arthritis in mice
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DOI：
10.1002/art.22602
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发表时间：
2007-06-01
影响因子：
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通讯作者：
Roecken, Martin
中科院分区：
文献类型：
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作者：
Kneilling, Manfred;Hueltner, Lothar;Roecken, Martin
客观的。用抗葡萄糖-6-磷酸异构酶 (GPI) 的自身抗体诱导关节炎完全独立于 T 细胞和 B 细胞，但严格依赖于肥大细胞的存在。在这里，我们使用这种疾病模型来分析单独的关节内肥大细胞重建是否足以诱导疾病，以及靶向肥大细胞沉默是否可以预防新血管生成和关节破坏（类风湿性关节炎的两个标志）。方法。通过腹膜内或选择性关节内注射，在野生型 Kit(+)/Kit(+) 小鼠、同源肥大细胞缺陷 Kit(W)/Kit(W-v) 小鼠或用肥大细胞重建的肥大细胞缺陷 Kit(W)/Kit(W-n) 小鼠中注射 K/BxN 小鼠血清或对照血清后，测定踝关节肿胀和临床指数评分。通过使用 F-18-半乳糖-RGD 和正电子发射断层扫描测量激活的 α v β 3 整合素来量化体内血管生成。此外，还用苏木精和伊红、吉姆萨、β 3 和α-肌动蛋白对关节组织进行染色。在 C57BL/6 或 BALB/c 小鼠中研究了色甘酸或沙丁胺醇治疗对肥大细胞稳定的影响。结果。比较野生型小鼠、肥大细胞缺陷的 Kit(W)/Kit(W-v) 小鼠和肥大细胞重建的 Kit(W)/Kit(W-v) 小鼠，我们首先表明，关节内和腹膜内肥大细胞植入完全恢复了对抗体诱导的关节炎、血管生成和 α v beta 3 整合素激活的易感性。重要的是，用沙丁胺醇或色甘酸选择性沉默肥大细胞可以防止αvβ3整合素激活、血管生成和关节破坏。结论。肥大细胞植入完全恢复 GPI 抗体诱导的关节炎中对 α v β 3 整合素激活、血管生成和关节破坏的敏感性。重要的是，选择性肥大细胞稳定可防止 α v beta 3 整合素激活、血管生成和关节破坏。
Objective. Induction of arthritis with autoantibodies against glucose-6-phosphate isomerase (GPI) is entirely independent of T cells and B cells but is strictly dependent on the presence of mast cells. Here, we used this disease model to analyze whether exclusive intraarticular mast cell reconstitution is sufficient for disease induction and whether targeted mast cell silencing can prevent neoangiogenesis and joint destruction, 2 hallmarks of rheumatoid arthritis.Methods. Ankle swelling and clinical index scores were determined after injection of either K/BxN mouse-derived serum or control serum in wild-type Kit(+)/Kit(+) mice, congenic mast cell-deficient Kit(W)/Kit(W-v) mice, or mast cell-deficient Kit(W)/Kit(W-n) mice reconstituted with mast cells, either by intraperitoneal or selective intraarticular injection. Angiogenesis was quantified in vivo by measuring activated alpha v beta 3 integrin using F-18-galacto-RGD and positron emission tomography. In addition, staining of joint tissue with hematoxylin and eosin, Giemsa, beta 3, and alpha-actin was performed. The effect of mast cell stabilization by treatment with cromolyn or salbutamol was investigated in C57BL/6 or BALB/c mice.Results. Comparing wild-type mice, mast cell-deficient Kit(W)/Kit(W-v) mice, and mast cell-reconstituted Kit(W)/Kit(W-v) mice, we first showed that intraarticular and intraperitoneal mast cell engraftment fully restores susceptibility to antibody-induced arthritis, angiogenesis, and alpha v beta 3 integrin activation. Importantly, selective mast cell silencing with either salbutamol or cromolyn prevented alpha v beta 3 integrin activation, angiogenesis, and joint destruction.Conclusion. Mast cell engraftment fully restores susceptibility to alpha v beta 3 integrin activation, angiogenesis, and joint destruction in GPI antibody-induced arthritis. Importantly, selective mast cell stabilization prevents alpha v beta 3 integrin activation, angiogenesis, and joint destruction.