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Fucosyltransferase 1 mediates angiogenesis in rheumatoid arthritis.

Isozaki T, Amin MA, Ruth JH, Campbell PL, Tsou PS, Ha CM, Stinson WA, Domino SE, Koch AE.

Arthritis Rheumatol. 2014;66(8):2047-58.

University of Michigan, Ann Arbor.

 

Abstract

Glycosylation is a post-translational modification of proteins, and fucosylation, a type of glycosylation, has been previously demonstrated to have clinical relevance in cancer and inflammatory disorders such as rheumatoid arthritis (RA). Fucosylation affects the biological functions of not only inflammatory cytokines but adhesion molecules and growth factor receptors as well. In this study, we identified a role for fucosyltransferase 1 (fut1), one of the primary enzymes responsible for fucosylation in the RA joint, to induce angiogenesis in RA synovial tissue (ST).

 We initially showed the expression of α(1,2)-linked fucosylated proteins on endothelial cells (ECs) in the RA synovium. The amount of ECs and the percentage of these cells expressing fucosylated proteins were significantly elevated compared to osteoarthritis (OA) and normal STs. We also found that α(1,2)-linked fucosylated monocyte chemoattractant protein-1 (MCP-1/CCL2), a chemokine important for monocyte recruitment from the peripheral blood (PB) to RA ST, was present in RA synovial fluids (SFs), and was significantly higher compared to OA SF. These findings suggest that α(1,2)-linked fucosylated proteins, such as inflammatory chemokines, may have enhanced chemotactic and angiogenic activity in RA tissues compared to non-α(1,2)-linked fucosylated proteins.

 Fut1 is also a well described α(1,2)-fucosyltransferase responsible for synthesis of the H blood group and Lewisy antigens. We previously demonstrated that soluble H and Lewisy antigens could mediate inflammatory cell adhesion and angiogenesis in RA. Therefore, by blocking fut1 expression in human dermal microvascular ECs (HMVECs), we examined whether ECs would show reduced migratory (by in vitro chemotaxis assay) and/or angiogenic (by forming less tubes in the in vitro Matrigel assay) activity in response to vascular endothelial growth factor (VEGF), a potent angiogenic stimulus. By inhibiting fut1 expression in HMVECs using anti-sense oligonucleotides, we could show significantly reduced MCP-1/CCL2 and regulated on activation, normal T cell expressed and secreted (RANTES/CCL5) from transfected compared to non-treated ECs. We confirmed these findings using mouse lung endothelial cells (MLECs) isolated from either fut1 deficient or wild type mice, and found that MLECs unable to express fut1 displayed significantly reduced MCP-1/CCL2 production in culture. Overall, we showed the importance of α(1,2)-linked fucosylation by fut1 in RA angiogenesis, and our findings suggest that fut1 may be an exciting new target for angiogenic diseases like RA.

 Copyright © 2014 by the American College of Rheumatology.

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