The Role of Angiopoietin-1 in Rheumatoid Arthritis

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DESCRIPTION (provided by applicant): Angiogenesis is a critical component of the inflammation associated with rheumatoid arthritis (RA). The longterm goals of the proposed studies are to understand the molecular mechanisms underlying angiogenesis in RA and thereby identify novel therapeutic approaches to treating inflammatory arthritis. Angiogenesis is a complex, multistep process that eventually leads to the development of mature blood vessels. Several angiogenic growth factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been identified within the rheumatoid synovium, all of which promote the early steps of angiogenesis. Recently, a novel angiogenic factor, Angiopoietin-1(Ang-1) was identified, that has the unique properties of facilitating the later stages of angiogenesis. We have determined that Ang-1 is expressed in synovial fibroblasts derived from patients with RA. Furthermore, proinflammatory cytokines can markedly upregulate the expression of Ang-1 in these cells and induce Ang-1 in other cell types found in the rheumatoid synovium including monocytes and chondrocytes. In addition to its role in promoting vessel maturation Ang-1 is a potent chemoattractant. The strong expression of Ang-1 in synovial fibroblasts may facilitate the migration of endothelial cells to the growing pannus. The molecular mechanisms by which Ang-1 mediates its effects in endothelial cells are poorly understood. We have also determined that the Ets factor NERF2 is induced by Ang- 1 in endothelial cells suggesting that NERF2 is a transcriptional regulator of Ang-1 mediated effects. The hypothesis for this proposal is that Ang-1 is one of the critical factors required for the angiogenic response in rheumatoid arthritis. The goals of this grant application are to define the biological role of Ang- 1 in promoting the angiogenic component of inflammatory arthritis, to further define the biological role of NERF2 as a transcriptional mediator of Ang- 1, and examine the therapeutic potential of blocking Ang- 1 during the development of inflammatory arthritis. Thus the Specific Aims are to determine: 1. What is the biological role of Ang-1 in inflammatory arthritis? 2. What is the role of the Ets transcription factor NERF2, in mediating the biological effects of Ang-1? 3. What is the therapeutic effect of blocking the function of Ang-1 in inflammatory arthritis? The approaches that will be used to address these questions include immunohistochemistry, in situ hybridization, the examination of synovial tissue samples from patients with RA and animals with collagen induced arthritis, adenoviral and retroviral gene delivery methods, assays of endothelial function, and flow cytometry.