Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo
Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo
复制标题
DOI：
10.1002/art.22061
复制
发表时间：
2006-09-01
影响因子：
--
通讯作者：
Salmi, Marko
中科院分区：
文献类型：
--
作者：
Marttila-Ichihara, Fumiko;Smith, David J.;Salmi, Marko
目标。白细胞从血液到关节的运输在关节炎的发病机制中是至关重要的。一种双功能的内皮细胞表面糖蛋白，AOC3（胺氧化酶，含铜3；也称为血管粘附蛋白1），具有粘附和酶的特性。我们进行了这项研究，以确定AOC3及其氧化酶活性在体内炎症关节白细胞运输中的作用。我们使用基因修饰动物、分子模型、AOC3酶抑制剂、氧化酶测定和关节炎模型（大鼠佐剂诱导关节炎[AIA]和小鼠抗II型胶原抗体诱导关节炎）来解剖AOC3在体内的重要性。AOC3抑制剂与AOC3晶体结构的活性位点具有共价结合模式。在酶分析中，它选择性地阻断了AOC3氧化酶的活性。腹腔和口服AOC3抑制剂可显著改善大鼠AIA。在抗II型胶原抗体诱导的小鼠关节炎中，AOC3抑制剂也改善了关节炎症的结局。该抑制剂阻断急性氨基脲敏感胺氧化酶的效果甚至比AOC3基因缺失更明显。酶分析表明，该抑制剂还能阻断另外2种结构上非常接近的AOCs，但对其他100多种酶没有阻断作用。这些数据首次证明了非典型内皮粘附分子AOC3的酶活性，以及其他密切相关的外氧化酶活性，对于体内炎症关节血管中的白细胞退出至关重要。
Objective. Leukocyte traffic from the blood to the joints is crucial in the pathogenesis of arthritis. A bifunctional endothelial cell-surface glycoprotein, AOC3 (amine oxidase, copper-containing 3; also known as vascular adhesion protein 1), has both adhesive and enzymatic properties. We undertook this study to determine the contribution of AOC3 and its oxidase activity to leukocyte trafficking into inflamed joints in vivo.Methods. We used gene-modified animals, molecular modeling, an AOC3 enzyme inhibitor, oxidase assays, and arthritis models (adjuvant-induced arthritis [AIA] in rats and anti-type II collagen antibody-induced arthritis in mice) to dissect the importance of AOC3 in vivo.Results. The AOC3 inhibitor fitted well with a covalent binding mode into the active site of the AOC3 crystal structure. It selectively blocked the oxidase activity of AOC3 in enzyme assays. Intraperitoneal and oral administration of the AOC3 inhibitor significantly ameliorated rat AIA. In anti-type II collagen antibody- induced arthritis in mice, the AOC3 inhibitor also improved the outcome of the joint inflammation. The acute semicarbazide-sensitive amine oxidase blockade by the inhibitor had even more pronounced effects than genetic deletion of AOC3. Enzymatic analyses showed that the inhibitor also blocked 2 other structurally very closely related AOCs, but not any of more than 100 other enzymes tested.Conclusion. These are the first data to demonstrate that the enzymatic activity of the atypical endothelial adhesion molecule AOC3, and possibly that of other closely related ecto-oxidases, is crucial for leukocyte exit from the vessels in inflamed joints in vivo.