Inhibition of rheumatoid synovial fibroblast proliferation by antisense oligonucleotides targeting proliferating cell nuclear antigen messenger RNA

OBJECTIVE: To evaluate the feasibility of antisense oligonucleotides as therapeutic agents to inhibit synovial cell growth in rheumatoid arthritis (RA). METHODS: Fibroblast-like cells established from RA synovium were stimulated with interleukin-1beta (IL-1beta) and treated with antisense or sense oligonucleotides targeting proliferating cell nuclear antigen (PCNA) messenger RNA (mRNA). Proliferation of these cells was determined by 3H-thymidine incorporation. Effects of antisense oligonucleotides on the expression of mRNA and protein were evaluated by reverse transcriptase-polymerase chain reaction and immunohistochemical staining, respectively. RESULTS: Antisense oligonucleotides targeting PCNA inhibited IL-1-stimulated fibroblast proliferation, whereas sense oligonucleotides had no effect. Both mRNA and protein levels of PCNA were suppressed in the cells treated with antisense oligonucleotides, indicating that the antiproliferative effect was occurring through an antisense mechanism. CONCLUSION: These results suggest that antisense strategies designed to suppress PCNA expression have potential use as therapeutic agents for RA.