Angiogenesis is likely to play a key role in the pathogenesis of inflammatory arthritis. Several angiogenicmolecules, including vascular endothelial growth factor and angiopoietin 1, are increased during rheumatoidarthritis (RA), and inhibition of angiogenesis suppresses arthritis in animal models, such as collagen-inducedarthritis (CIA). We recently identified a pro-angiogenic gene, angiopoietin-like 4 (Angptl4), as the seventhmost highly over-expressed mRNA in arthritic paws of mice with CIA. Expression of human Angptl4 mRNAwas also substantially increased in human arthritic synovium. Angiopoietin-like 4 (Angptl4) is structurally andfunctionally 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 tissueand inflamed synovium. This limited tissue distribution suggests that Angptl4 may play a distinct angiogenicrole in arthritic tissue. Specific targeting of angiogenic events occurring within arthritic synovium may befavorable therapeutically. Angptl4 binds endothelial cells and can induce tubule formation of endothelial cellsin vitro. Since Angptl4 binds to and exerts specific effects on endothelial cells, it is highly likely that areceptor for Angptl4 on endothelial cells mediates these effects. Therefore, Angptl4 and its putative receptorrepresent a major, targetable axis in the treatment of inflammatory arthritis. In this proposal we will developthe key reagents needed to test the hypothesis that Angptl4 increases inflammatory processes bypromoting angiogenesis in arthritic synovial tissues. We directly test this hypothesis by (1) determining theeffects of Angptl4 depletion on arthritis in the CIA mouse model and by (2) identifying and characterizing thereceptor(s) for Angptl4 on endothelial cells.
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