The joints in arthritis are characterized by inflammatory cell infiltration, expansion of synovial cells and pannus formation, resulting in destruction of cartilage and bone. Angiogenesis plays a critical role in the pathogenesis of the disease. Neovascularization is required not only to maintain this tumor-like mass in the arthritic joint but also to play an active role in inflammation as a source of both cytokines and proteases and for inflammatory cell adhesion and infiltration. Therefore, activated endothelium in the inflammatory joint is a promising target for therapeutic intervention. Tie2 and VEGF receptor (VEGFR) are two endothelium- specific receptor tyrosine kinases. VEGFR and Tie2 work in a complementary and coordinated fashion to regulate vascular formation and function. It is also increasingly evident that these angiogenic factors also regulate inflammation and have effects that extend beyond these conventionally defined roles. VEGF/ VEGFR and Ang/Tie2 (Ang is the ligand forTie2) are elevated in patients and contribute to vascular inflammation, angiogenesis and arthritis progression. Recently, we found that neutralizing Tie2 function prevents bone from erosion in arthritis joints presumably via downregulation of RANKL. In addition, the expression of Ang/Tie2 and VEGFA/EGFR is coordinately induced in synoviocytes and endothelial cells (ECs) by TNF-alpha, a key cytokine in the inflammatory joint, illustrating an intimate interaction between these two cellular components. Based on these, we hypothesize that Tie2 and VEGFR signaling jointly regulates endothelial activation, EC-synoviocyte and EC-osteoclast interaction that lead to vascular inflammation, angiogenic response, bone erosion and disease development in arthritis joints. This proposed study will investigate the interaction and coordination of Ang/Tie2 and VEGFA/EGFR signals in these pathological processes.
Our specific aims are: 1). Investigate the interactive effects of Ang & VEGF in vascular inflammation, EC-osteoclast interaction and osteoclast maturation using in vitro co-culture assays; 2) Examine the interactive effects of Ang & VEGF in leukocyte and osteoclast infiltration and maturation, angiogenesis and vascular survival using an in vivo synovium vascular window model; 3) Identify the role of Tie2 and VEGFR signaling in synovial inflammation, angiogenesis, bone erosion and disease development using a chronic arthritis animal model coupled with novel non-invasive imaging approaches. ? ? ?
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