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The angiogenic factor VEGF promotes synovitis and bone erosion in rheumatoid arthritis (RA). Previously, we have demonstrated that VEGF expression correlates with disease severity in RA patients and in murine collagen-induced arthritis (CIA). In this study, we adopted an adenoviral gene delivery system expressing soluble VEGF receptor 1 (sFlt-1) to further study the role of VEGF in CIA. Arthritis was induced in DBA/1 mice by injection of bovine collagen. Adenoviruses expressing human soluble VEGF receptor 1 (AdvsFlt-1), or without transgene (Adv0), were injected intravenously on the first day of arthritis. We found that disease severity and paw swelling were significantly suppressed in mice receiving AdvsFlt-1, when compared to untreated or Adv0-treated mice. Expression of sFlt-1 peaked 24 h after injection, with protein detectable in the liver, synovial issue and serum, but rapidly decreased by 72 h. The effect of sFlt-1 expression on signs of disease was paralleled by reduced joint destruction and decreased expression of the vascular marker von Willebrand factor. In summary, adenoviral delivery of human soluble VEGF receptor type 1 significantly suppressed disease activity in CIA. The actions of AdvsFlt-1 are likely to be mediated by reduced synovial neovascularization, and these results support the concept that VEGF blockade may be an effective therapeutic adjunct for the treatment of RA.

Original publication

DOI

10.1038/sj.gt.3302104

Type

Journal article

Journal

Gene therapy

Publication Date

11/2003

Volume

10

Pages

1950 - 1960

Addresses

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.

Keywords

Joints, Synovial Membrane, Cells, Cultured, Fibroblasts, Animals, Humans, Mice, Adenoviridae, Arthritis, Experimental, Nonmuscle Myosin Type IIB, Vascular Endothelial Growth Factor A, Proteins, von Willebrand Factor, Myosin Heavy Chains, Membrane Proteins, Extracellular Matrix Proteins, Antibodies, Viral, Blotting, Western, Gene Therapy, Transduction, Genetic, Gene Expression, Genetic Vectors