Angiogenesis and the Persistence of Inflammation in a Rat Model of Proliferative Synovitis

Objective. To determine whether blood vessel growth at the onset of resolving synovitis leads to its subsequent persistence and whether inhibiting this angiogenesis at the onset of persistent inflammation leads to its subsequent resolution. Methods. Inflammation and angiogenesis were induced by injection of 0.03% carrageenan and/or 6 pmoles of fibroblast growth factor 2 (FGF-2) into rat knees. A brief treatment with the angiogenesis inhibitor PPI-2458 (5 mg/kg orally on alternate days) was administered 1 day before and up to 3 days after synovitis induction. Controls comprised naive and vehicle-treated rats. Synovial angiogenesis was measured using the endothelial cell proliferation index, and inflammation was determined by measuring joint swelling and macrophage percentage area. Data are presented as the geometric mean (95% confidence interval). Results. Intraarticular injection of 0.03% carrageenan into rat knees produced acute synovitis, which was not associated with synovial angiogenesis and which resolved within 29 days. Injection of FGF-2 (6 pmoles) induced synovial angiogenesis without significant synovitis. Stimulation of angiogenesis with FGF-2 at the time of carrageenan injection was followed by synovitis that persisted for 29 days. Persistence of carrageenan/FGF-2-induced synovitis was prevented by systemic administration of 3 doses of the angiogenesis inhibitor PPI-2458 during the acute phase. Conclusion. Our findings indicate that conversion of acute inflammation to chronic inflammation may be due to the stimulation of angiogenesis, and brief antiangiogenic treatment during the acute phase of synovitis may prevent its subsequent progression. Clinical studies will be needed to determine whether brief antiangiogenic treatment may reduce the burden of inflammatory joint diseases such as rheumatoid arthritis by facilitating the resolution of early synovitis.