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Vascular Endothelial Growth Factor Expression in Arthritic Joint Is Regulated by SAF-1 Transcription Factor¹

Bimal K. Ray^*,, Arvind Shakya^* and Alpana Ray^2,*,

^* Department of Veterinary Pathobiology and Department of Orthopaedic Surgery, University of Missouri, Columbia, MO 65211

Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of arthritis by promoting angiogenesis in the synovial joint and infiltration of inflammatory cells in the synovial joint. Although ample information has been obtained on the mechanism of VEGF regulation during cancer and hypoxic condition, less is known about the control of VEGF expression during arthritis. From the studies on the experimentally induced arthritis in a transgenic mouse model that overexpresses a transcription factor, serum amyloid A activating factor-1 (SAF-1), leading to markedly higher levels of angiogenesis, synovial inflammation, and inflammatory cell infiltration, we have identified a novel mechanism of VEGF regulation. We present molecular evidence that VEGF expression is increased in SAF-1-transgenic mice and that SAF-1 induces VEGF transcription by directly binding to its promoter. Deletion of SAF-1 binding elements from the VEGF promoter as well as knockdown of endogenous SAF-1 markedly inhibited IL-1- and TGF--mediated induction of VEGF expression in chondrocyte cells. By chromatin immunoprecipitation assay, in vivo, markedly higher levels of SAF-1 interaction with the VEGF promoter was detected in the cartilage tissues of arthritic mice as well as human osteoarthritic patients. Together, these results provide a new insight into the molecular mechanism of VEGF expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by U.S. Public Health Service Grant AR48762.

² Address correspondence and reprint requests to Dr. Alpana Ray, Department of Veterinary Pathobiology, University of Missouri, 126A Connaway Hall, Columbia, MO 65211. E-mail address: rayal{at}missouri.edu

³ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; OA, osteoarthritis; HIF, hypoxia-inducible factor; SAF-1, serum amyloid A activating factor-1; ChIP, chromatin immunoprecipitation; CAT, chloramphenicol acetyl transferase.