Targeting rheumatoid tenosynovial angiogenesis with cytokine inhibitors

Proliferation and invasion of the tenosynovial lining of tendons in patients with rheumatoid arthritis can result in tendon damage and rupture, leading to decreased hand function. Angiogenesis is an important process in rheumatoid joint disease; however, the role of angiogenesis in tendon disease is unknown. Our aim was to determine whether rheumatoid tenosynovial lining could produce angiogenic proteins, and if inhibition of tumor necrosis factor-alpha and interleukin-1 could decrease vascular endothelial growth factor production. Samples of encapsulating and invasive tenosynovial lining taken from the same hand and wrist synovial lining were harvested from 58 patients with rheumatoid arthritis having wrist surgery. Ex vivo samples were studied to quantify vascularity, angiogenic protein production under normoxic and hypoxic conditions, and the effect of inhibiting tumor necrosis factor-alpha and interleukin-1 on vascular endothelial growth factor production. Rheumatoid tenosynovial lining was more vascular than rheumatoid joint synovial lining and produced high levels of angiogenic factors such as vascular endothelial growth factor, interleukin-1 beta, fibroblast growth factor-2, and angiopoietin-2. Hypoxia induced an increase in production of vascular endothelial growth factor by ex vivo tenosynovial lining cells. Inhibition of the cytokines interleukin-1 and tumor necrosis factor-alpha effectively reduced vascular endothelial growth factor production by tenosynovial samples.