New cyclooxygenase-2 inhibitor DFU regulates vascular endothelial growth factor expression in rheumatoid synoviocytes

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in rheumatoid synoviocytes. In the present study, whether DFU, a tetrasubstituted furanone initially identified as a selective inhibitor of cyclooxygenase (COX)-2, interferes with transforming growth factor (TGF)-beta-mediated induction of VEGF was determined. Fibroblast-like synoviocytes (FLS) isolated from the synovial tissue of patients with rheumatoid arthritis were stimulated with TGF-beta in the presence or absence of DFU, followed by RT-PCR and ELISA assays to quantify the level of VEGF transcript and its product, respectively. DFU was found to elicit diverse activities on FLS, including inhibition of COX-2 and VEGF expression as well as COX-2 activity. The inhibition of TGF-beta-induced VEGF production by DFU was dose-dependent and abolished by exogenous prostaglandin E,. DFU was more potent than indomethacin to inhibit the VEGF production. These results suggest an in vivo potential for DFU to regulate both processes of inflammation and angiogenesis which collaboratively play important roles in the progression and perpetuation of rheumatoid arthritis. (C) 2004 Elsevier B.V. All rights reserved.