Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis

Maintenance of the invasive pannus in rheumatoid arthritis is an integral p art of disease progression. The synovial vasculature plays an important rol e in the delivery of nutrients, oxygen, and inflammatory cells to the synov ium. Vascular endothelial growth factor (VEGF), an endothelial mitogen expr essed by cells within the synovial membrane, is thought to contribute to th e formation of synovial blood vessels. Our objective in this study was to m easure the kinetics of VEGF production in a murine model of collagen-induce d arthritis and to determine whether VEGF blockade reduces disease progress ion. Synovial cells isolated from the knee joints of naive or sham-immunize d mice, or from mice immunized with collagen but without arthritis, release d little or no detectable VEGF. Onset of arthritis was associated with expr ession of VEGF mRNA and protein. The levels of VEGF secreted by synovial ce lls isolated from the joints of mice with severe arthritis were significant ly higher than from mice with mild disease. To block VEGF activity, animals were treated after arthritis onset with a soluble form of the Flt-1 VEGF r eceptor (sFlt), which was polyethylene glycol (PEG)-linked to increase its in vivo half-life. Treatment of arthritic mice with sFlt-PEG significantly reduced both clinical score and paw swelling, compared with untreated or co ntrol-treated (heat-denatured sFlt-PEG) animals. There was also significant ly less joint inflammation and reduced bone and cartilage destruction in sF lt-PEG-treated animals, as assessed by histology. Our data demonstrate that , in collagen-induced arthritis, expression of the potent angiogenic cytoki ne VEGF correlates with disease severity. Furthermore, specific blockade of VEGF activity results in attenuation of arthritis in both macroscopic and microscopic parameters. These observations indicate that blood vessel forma tion is integral to the development of arthritis and that blockade of VEGF activity might be of therapeutic benefit in rheumatoid arthritis.