Inhibition of CCR1/CCR5 mediated angiogenesis and joint destruction by EGCG

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DESCRIPTION (provided by applicant): PROJECT SUMMARY Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which activated synovial fibroblasts produce chemokines that facilitate the invasion of the articular cartilage and underlying bone by the release of matrix-degrading enzymes. Importantly, RANTES/CCL5 and macrophage inflammatory protein (MIP-11)/CCL3 are the chemokines shown to activate CCR1 and CCR5 receptor to attract T cells and monocytes into joints during the onset of disease. Thus, regulation of CCR1/CCR5 receptor expression is emerging as a novel therapeutic strategy for RA. In our preliminary findings, epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory molecule, blocked interleukin-12 (IL-12)-induced RANTES/CCL5 and MIP-11/CCL3 ) production in RA synovial fibroblasts that are mediated via CCR1/CCR5 receptors. EGCG also inhibited IL-12-induced markers of cartilage and bone destruction (IL-6, VEGF, and PGE2), and matrix degrading enzyme matrix metalloproteinase-2 (MMP-2) activity in human RA synovial fibroblasts. [An in vivo study showed that EGCG prevented adjuvant-induced arthritis (AIA) in rats.] This proposal capitalizes on these novel observations. The central hypothesis of the work proposed is that EGCG inhibits cell recruitment, angiogenesis and joint destruction in rat adjuvant-induced arthritis (AIA) model and in RA synovial tissue (ST)-severe combined immunodeficient (SCID) chimera by blocking CCR1/CCR5 receptor expression. In Aim 1, we will test whether EGCG inhibits CCR1/CCR5 receptor expression to suppress RANTES/CCL5 or MIP-11/CCL3 activity and angiogenesis in RA ST explants. In Aim 2, we will study if EGCG blocks CCR1/CCR5 receptor mediated cell recruitment and tissue invasion in a human RA ST- severe combined immunodeficiency (SCID) mouse chimera. Finally, in Aim 3, we will determine whether EGCG downregulates CCR1/CCR5 receptor expression to inhibit angiogenesis, and cartilage and bone destruction in a rat AIA model of RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potential treatment option for RA and possibly other autoimmune diseases. PROJECT NARRATIVE Rheumatoid arthritis (RA), a chronic inflammatory joint disorder, is a leading cause of work-related disabilities and a significant socio-economic health challenge due to expensive, yet incomplete, conventional therapies. Using animal models of human RA, we propose to test the efficacy of epigallocatechin-3-gallate (EGCG), a potential anti-inflammatory molecule found in green tea, in inhibiting the destruction of the cartilage and bone in RA. The success of the proposed experiments may lead to a significant advancement in the development of EGCG as a potentially safe and inexpensive treatment option for RA.