Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo

University of Turku, and National Public Health Institute, Turku, Finland.
Arthritis & Rheumatology (Impact Factor: 7.76). 09/2006; 54(9):2852-62. DOI: 10.1002/art.22061
Source: PubMed


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.
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.
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.
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.

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Available from: Craig M Stolen, Sep 30, 2015
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    • "These mice show faster rolling (less efficient leukocyte-endothelial cell contacts), reduced number of firmly adherent cells, and a clear inhibition of leukocyte transmigration into sites of inflammation. Moreover, inflammatory reactions such as peritonitis and arthritis, and responses to mucosal immunization are attenuated in the absence of VAP-1 [38] [49]. VAP-1 also seems to contribute to leukocyte homeostasis in the fat tissue. "
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    • "VAP-1 is practically absent from the endothelial surface of normal tissues; however, upon infection/inflammation, it is translocated from intracellular sources to the cell surface [10]. For instance, dermal blood vessels in various skin inflammatory diseases (e.g., psoriasis), gut blood vessels in inflammatory bowel diseases (e.g., Crohn's disease) and synovial blood vessels in inflamed joints (e.g., rheumatoid arthritis) start to express VAP-1 on their surface [13] [14]. In addition to endothelial cells, VAP-1 is present in smooth muscle cells, adipocytes and follicular dendritic cells [15]. "
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