OBJECTIVE: To elucidate whether the microRNA (miRNA) cluster miR-17-92 
contributes to the activated phenotype of rheumatoid arthritis synovial 
fibroblasts (RASFs).
METHODS: RASFs were stimulated with tumor necrosis factor α (TNFα), and the 
expression and regulation of the miR-17-92 cluster were studied using real-time 
quantitative PCR (PCR) and promoter activity assays. RASFs were transfected with 
single precursor molecules of miRNAs from miR-17-92 and the expression of 
matrix-degrading enzymes and cytokines was measured by quantitative PCR and 
enzyme-linked immunosorbent assay. Potential miRNA targets were identified by 
computational prediction and were validated using reporter gene assays and 
Western blotting. The activity of NF-κB signaling was determined by reporter 
gene assays.
RESULTS: We found that TNFα induces the expression of miR-17-92 in RASFs in an 
NF-κB-dependent manner. Transfection of RASFs with precursor molecules of single 
members of miR-17-92 revealed significantly increased expression levels of 
matrix-degrading enzymes, proinflammatory cytokines, and chemokines in precursor 
miR-18a (pre-miR-18a)-transfected RASFs. Using reporter gene assays, we 
identified the NF-κB pathway inhibitor TNFα-induced protein 3 as a new target of 
miR-18a. In addition, pre-miR-18a-transfected RASFs showed stronger activation 
of NF-κB signaling, both constitutively and in response to TNFα stimulation.
CONCLUSION: Our data suggest that the miR-17-92-derived miR-18a contributes to 
cartilage destruction and chronic inflammation in the joint through a positive 
feedback loop in NF-κB signaling, with concomitant up-regulation of 
matrix-degrading enzymes and mediators of inflammation in RASFs.