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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR055741-02
Application #
7646209
Study Section
Special Emphasis Panel (ZAR1-EHB-H (M1))
Program Officer
Mao, Su-Yau
Project Start
2008-07-01
Project End
2009-06-30
Budget Start
2009-05-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2009
Total Cost
$8,652
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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