**4.3 S1P receptor expression in RA synovial fibroblasts**

In RA, the abnormal growth and erosive activity of synovial fibroblasts suggest that these cells are important contributors to chronic inflammation. During RA disease progression, synovial fibroblasts become hyperplasic and closely interact with infiltrated immune cells to form the aggressive pannus tissue that eventually promotes joint destruction (reviewed in (Feldmann et al., 1996a)). Synovial fibroblasts have been reported to express three of five known S1P receptors, S1P1-3 (Kitano et al., 2006; Nochi et al., 2008; Zhao et al., 2008). Expression of S1P1 in RA synovial tissues was significantly higher compared to that of OA synovial tissues (Kitano et al., 2006). Moreover, pretreatment of synovial fibroblasts with TNF-, the well-recognized critical cytokine in RA, resulted in up-regulation of S1P3 receptor expression in synovial fibroblasts, which likely contributes to the synergistic production of inflammatory cytokines/chemokines upon subsequent exposure to S1P (Zhao et al., 2008).
