Rheumatoid arthritis (RA) is an autoimmune disease characterized by the activation of synovial fibroblasts that produce chemokines to facilitate infiltration of inflammatory cells into the synovial tissue, leading to pannus formation and progressive bone and cartilage erosion. The molecular mechanisms that initiate RA are not yet known. Current treatments provide only symptomatic relief by alleviating pain and reducing disease progression. RANTES (Regulated on activation, T cell expression and secreted)/CCL5 is a C-C chemokine that participates in RA pathogenesis by facilitating leukocyte infiltration in affected joints. However, the impact of RANTES on gene regulation, cell proliferation, and tissue destruction in RA is not fully defined. The results of our studies provide evidence that RANTES/CCL5 induces synovial hyperplasia and cartilage and bone erosion in joints through the expression of matrix metalloproteinases (MMPs) and by upregulating PKCdelta, JNK, and ERK pathways in human RA synovial fibroblasts (RASFs). Furthermore, our findings provide evidence of the novel role of syndecans (SDC), type I transmembrane heparan sulfate proteoglycans, in promoting RANTES/CCL5-, TNF-alpha, or IL-1beta-mediated inflammation and tissue destruction in RA. In particular, we identified pivotal roles for SDC2 and SDC4 in RA pathogenesis. Finally, we also investigated the therapeutic potential of epigallocatechin-3-gallate (EGCG), a potent anti-inflammatory compound found in green tea. EGCG ameliorated RANTES/CCL5-syndecan mediated tissue destruction, which correlated with a decrease in SDC-2 and SDC-4 expression. These findings provide rationale for targeting SDCs using EGCG or its structural analogs as a novel therapeutic strategy to suppress cytokine/chemokine mediated inflammation and tissue destruction in RA.