Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis
Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis
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DOI：
10.4049/jimmunol.171.9.4853
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发表时间：
2003-11-01
影响因子：
4.4
通讯作者：
Pasquier, C
中科院分区：
文献类型：
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作者：
De Bandt, M;Ben Mahdi, MH;Pasquier, C
血管内皮生长因子（VEGF）是一种内皮细胞生长因子，在类风湿性关节炎中起着重要作用。VEGF与特异性受体VEGF-RI和VEGF-RII结合。我们评估了选择性阻断VEGF及其受体在转基因K/BxN小鼠中的物理和组织学效应，这是一种非常接近人类疾病的类风湿性关节炎模型。用抗小鼠VEGF Ab、抗小鼠VEGF-RI和VEGF-RII Ab以及VEGF-RI酪氨酸激酶抑制剂处理小鼠。使用临床指标和组织学检查监测疾病活动。我们发现关节炎关节的滑膜细胞表达VEGF、VEGF-RI和VEGF-RII。在整个研究期间，用抗VEGF-RI治疗强烈减弱了疾病，而抗VEGF仅短暂延迟疾病发作。用抗VEGF-RII治疗没有效果。抗VEGF-RI减轻了临床表现的强度，并且基于定性和血清定量组织学分析，防止了关节损伤。用VEGF-RI酪氨酸激酶抑制剂治疗几乎消除了这种疾病。这些结果表明，VEGF是血管翳发展的关键因素，通过VEGF-RI途径起作用。体内施用靶向VEGF-RI通路的特异性抑制剂抑制关节炎并防止骨破坏的观察结果为治疗类风湿性关节炎开辟了新的可能性。
It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and serniquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.