ROLE OF ANGPTL4, AN ANGIOGENIC MEDIATOR, IN ARTHRITIS

血管生成可能在炎症性关节炎的发病机制中起关键作用。几种血管生成 包括血管内皮生长因子和血管生成素1在内的分子在类风湿疾病中升高 关节炎(RA)，抑制血管生成可抑制动物模型中的关节炎，如胶原诱导的关节炎 关节炎(CIA)。我们最近发现了一个促血管生成的基因，血管生成素样蛋白4(ANGPTL4)，是第七个 在CIA模型小鼠的关节炎足爪中，大多数基因高度过表达。人血管紧张素转换酶4基因的表达 在人类关节炎滑膜中也显著增加。血管生成素样蛋白4(ANGPTL4)在结构上和 在功能上类似于血管生成素，因为它特异性地抑制血管内皮细胞的凋亡。 ANGPTL4在小鼠和人类中的表达主要限于肝、肾、脂肪组织 滑膜发炎。这种有限的组织分布表明，ANGPTL4可能发挥着独特的血管生成作用 在关节炎组织中的作用。发生在关节炎滑膜内的血管生成事件的特定靶点可能是 在治疗上是有利的。ANGPTL4结合内皮细胞并诱导内皮细胞小管形成 在试管中。由于ANGPTL4与血管内皮细胞结合并对其发挥特殊作用，因此很可能是一种 内皮细胞上的ANGPTL4受体介导了这些效应。因此，ANGPTL4及其可能的受体 在炎症性关节炎的治疗中代表了一个主要的、有针对性的轴。在这份提案中，我们将制定 检验ANGPTL4通过以下途径增加炎症过程的假说所需的关键试剂 促进关节炎滑膜组织中的血管生成。我们通过以下方法直接检验这一假设：(1)确定 ANGPTL4耗竭对CIA小鼠模型关节炎的影响及(2)鉴定和表征 血管内皮生长因子受体(S)。

Angiogenesis is likely to play a key role in the pathogenesis of inflammatory arthritis. Several angiogenic molecules, including vascular endothelial growth factor and angiopoietin 1, are increased during rheumatoid arthritis (RA), and inhibition of angiogenesis suppresses arthritis in animal models, such as collagen-induced arthritis (CIA). We recently identified a pro-angiogenic gene, angiopoietin-like 4 (Angptl4), as the seventh most highly over-expressed mRNA in arthritic paws of mice with CIA. Expression of human Angptl4 mRNA was also substantially increased in human arthritic synovium. Angiopoietin-like 4 (Angptl4) is structurally and functionally similar to the angiopoietins, in that it specifically inhibits apoptosis of vascular endothelial cells. Expression of Angptl4 as assessed in mice and humans is limited primarily to liver, kidney, adipose tissue and inflamed synovium. This limited tissue distribution suggests that Angptl4 may play a distinct angiogenic role in arthritic tissue. Specific targeting of angiogenic events occurring within arthritic synovium may be favorable therapeutically. Angptl4 binds endothelial cells and can induce tubule formation of endothelial cells in vitro. Since Angptl4 binds to and exerts specific effects on endothelial cells, it is highly likely that a receptor for Angptl4 on endothelial cells mediates these effects. Therefore, Angptl4 and its putative receptor represent a major, targetable axis in the treatment of inflammatory arthritis. In this proposal we will develop the key reagents needed to test the hypothesis that Angptl4 increases inflammatory processes by promoting angiogenesis in arthritic synovial tissues. We directly test this hypothesis by (1) determining the effects of Angptl4 depletion on arthritis in the CIA mouse model and by (2) identifying and characterizing the receptor(s) for Angptl4 on endothelial cells.