Screening of Genes Regulating TNF-α-mediated Synovial Hyperplasia in Rheumatoid Arthritis

Chronic rheumatoid arthritis (RA) is characterized by the hyperplasia of synovial tissue, which results from the combined influence of the proliferation and antiapoptosis of the synovial cells. In this study, to identify candidate factors involved in the regulation of synovial hyperplasia, the expression profile of 205 apoptosis-related genes in a rheumatoid synovium was analyzed in comparison with that in an osteoarthritis (OA) synovium using a cDNA microarray. Upregulated genes in the RA synovium include TNFR2, GRB2, RBL2, CDC25B, MAPK p38, CDK-like kinase 2, and FLICE2, whereas 5 genes including SARP1 were down-regulated relative to OA. Among them, importantly, the expression levels of GRB2 and FLICE2 genes were remarkably enhanced in RA but not OA synoviocytes in response to TNF-α treatment. Therefore, TNF-α inducibility to GRB2 and FLICE2 genes abnormally enhanced in RA synoviocytes might represent the increased transcripts of these two genes in rheumatoid sunovial tissues. Moreover, these results suggest that RA-specific signals by TNF-α, including GRB2 and FLICE2, are involved in the pathogenic processes of synovial hyperplasia.