Background/Purpose: Angiogenesis is important in rheumatoid arthritis (RA) synovial tissue proliferation and leukocyte ingress into the inflamed joints. Fucosyltransferases (Futs) are involved in the synthesis of glycoconjugates and blood group antigens and other Futs have been shown to be important in inflammatory pathways such as leukocyte homing. Hence, we examined the role of another Fut, Fut1, in angiogenesis and leukocyte recruitment in inflammatory arthritis.

Methods: Mouse lung endothelial cells (ECs) from Fut1 null and wild type (wt) mice were used to perform Matrigel tube formation assays in vitro. We performed Matrigel plug in vivo angiogenesis assays using Fut1 null and wt mice. Some of the plugs were homogenized for hemoglobin determination while others were sectioned to perform immunofluorescence to count the number of blood vessels. To determine the contribution of Fut1-mediated angiogenesis and leukocyte recruitment in an animal model of arthritis, we performed the serum transfer K/BxN arthritis model employing Fut1 null and wt mice. Mouse ankles were measured before induction of arthritis and then on alternate days. Ankles were harvested on day 9, the day of maximum arthritis. Some of the arthritic ankles were homogenized to determine hemoglobin (Hb) while others were sectioned for blood vessel counts. To determine the mechanism of decreased leukocyte recruitment, we performed immunofluorescence for adhesion molecule expression in wt and Fut1 null mouse ankle sections. We stimulated Fut1 null and wt ECs and performed quantitative PCR and enzyme linked immunosorbent assays for adhesion molecule expression.

Results: Fut1 null ECs formed significantly less tubes compared to wt ECs on Matrigel. In the Matrigel plug in vivo angiogenesis assays, we found that Fut1 null mice had less Hb, an indirect measure of angiogenesis (four fold decrease) compared to wt mice. By immunofluorescence, wt mouse plugs formed significantly greater number of blood vessels. Fut 1 null mice were resistant to K/BxN arthritis showing a significant decrease in ankle circumference in comparison with wt mice. Fut1 null mouse arthritic ankle homogenates had less Hb, when compared to wt mice. Blood vessels formed in Fut1 null mouse ankle sections were four fold decreased compared to wt mouse ankle sections. This suggests that Fut1 plays a critical role in K/BxN arthritis development by modulating angiogenesis. Adhesion molecules are important in leukocyte recruitment into inflammatory sites. After finding decreased leukocytes in Fut1 null mouse sections, we examined the expression of adhesion molecules in arthritic mouse sections. By dual immunofluorescence, we found a marked decrease in intercellular adhesion molecule-1 (ICAM-1) in Fut1 null arthritic ankle sections. ICAM-1 expression was significantly decreased at both mRNA and protein levels in Fut1 null compared to wt mouse ECs, suggesting the mechanism of decreased leukocyte recruitment into the inflamed joint when Fut1 is absent.

Conclusion: These data suggest that Fut1 mediates inflammatory arthritis by modulating angiogenesis and may be a novel approach to treat angiogenesis-dependent diseases such as RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fut1-plays-a-unique-role-in-kbxn-serum-transfer-arthritis-by-regulating-angiogenesis-and-adhesion-molecule-expression/