Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis
Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis
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DOI：
10.1038/labinvest.3780127
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发表时间：
2000-08-01
影响因子：
5
通讯作者：
Paleolog, E
中科院分区：
文献类型：
--
作者：
Miotla, J;Maciewicz, R;Paleolog, E
类风湿关节炎侵袭性膜的维持是疾病进展的一个组成部分。滑膜血管系统在向滑膜输送营养物质、氧气和炎症细胞方面起着重要作用。血管内皮生长因子（VEGF）是一种由滑膜内细胞表达的内皮有丝分裂原，被认为有助于滑膜血管的形成。在这项研究中，我们的目的是测量小鼠胶原诱导关节炎模型中VEGF产生的动力学，并确定VEGF阻断是否会减少疾病进展。从未免疫或假免疫小鼠的膝关节分离的滑膜细胞，或从胶原免疫但没有关节炎的小鼠分离的滑膜细胞，释放很少或没有可检测到的VEGF。关节炎的发病与VEGF mRNA和蛋白的表达有关。从严重关节炎小鼠关节分离的滑膜细胞分泌的VEGF水平明显高于轻度关节炎小鼠。为了阻断VEGF活性，在关节炎发作后用可溶性形式的Flt-1 VEGF受体（sFlt）治疗动物，该受体是聚乙二醇（PEG）连接的，以增加其体内半衰期。与未治疗或对照治疗（热变性sFlt-PEG）的动物相比，用sFlt-PEG治疗关节炎小鼠的临床评分和脚掌肿胀均显著降低。通过组织学评估，sflt - peg处理的动物的关节炎症和骨和软骨破坏也明显减少。我们的数据表明，在胶原诱导的关节炎中，强效血管生成细胞因子VEGF的表达与疾病严重程度相关。此外，特异性阻断VEGF活性导致关节炎在宏观和微观参数上的衰减。这些观察结果表明，血管形成是关节炎发展不可或缺的一部分，阻断VEGF活性可能对类风湿关节炎有治疗益处。
Maintenance of the invasive pannus in rheumatoid arthritis is an integral part of disease progression. The synovial vasculature plays an important role in the delivery of nutrients, oxygen, and inflammatory cells to the synovium. Vascular endothelial growth factor (VEGF), an endothelial mitogen expressed by cells within the synovial membrane, is thought to contribute to the formation of synovial blood vessels. Our objective in this study was to measure the kinetics of VEGF production in a murine model of collagen-induced arthritis and to determine whether VEGF blockade reduces disease progression. Synovial cells isolated from the knee joints of naive or sham-immunized mice, or from mice immunized with collagen but without arthritis, released little or no detectable VEGF. Onset of arthritis was associated with expression of VEGF mRNA and protein. The levels of VEGF secreted by synovial cells isolated from the joints of mice with severe arthritis were significantly higher than from mice with mild disease. To block VEGF activity, animals were treated after arthritis onset with a soluble form of the Flt-1 VEGF receptor (sFlt), which was polyethylene glycol (PEG)-linked to increase its in vivo half-life. Treatment of arthritic mice with sFlt-PEG significantly reduced both clinical score and paw swelling, compared with untreated or control-treated (heat-denatured sFlt-PEG) animals. There was also significantly less joint inflammation and reduced bone and cartilage destruction in sFlt-PEG-treated animals, as assessed by histology. Our data demonstrate that, in collagen-induced arthritis, expression of the potent angiogenic cytokine VEGF correlates with disease severity. Furthermore, specific blockade of VEGF activity results in attenuation of arthritis in both macroscopic and microscopic parameters. These observations indicate that blood vessel formation is integral to the development of arthritis and that blockade of VEGF activity might be of therapeutic benefit in rheumatoid arthritis.