OBJECTIVE: To identify novel microRNA (miR) associations in synovial fibroblasts 
(SF), by performing miR expression profiling on cells isolated from the human 
tumour necrosis factor (TNF) transgenic mouse model (TghuTNF, Tg197) and 
patients biopsies.
METHODS: miR expression in SF from TghuTNF and wild-type (WT) control mice were 
determined by miR deep sequencing (miR-seq) and the arthritic profile was 
established by pairwise comparisons. Quantitative PCR analysis was utilised for 
profile validation, miR and gene quantitation in patient SF. Dysregulated miR 
target genes and pathways were predicted via bioinformatic algorithms and 
validated using gain-of-function coupled with reporter assay experiments.
RESULTS: miR-seq demonstrated that TghuTNF-SF exhibit a distinct pathogenic 
profile with 22 significantly upregulated and 30 significantly downregulated 
miR. Validation assays confirmed the dysregulation of miR-223, miR-146a and 
miR-155 previously associated with human rheumatoid arthritis (RA) pathology, as 
well as that of miR-221/222 and miR-323-3p. Notably, the latter were also found 
significantly upregulated in patient RA SF, suggesting for the first time their 
association with RA pathology. Bioinformatic analysis suggested Wnt/cadherin 
signalling as a putative pathway target. miR-323-3p overexpression was shown to 
enhance Wnt pathway activation and decrease the levels of its predicted target 
β-transducin repeat containing, an inhibitor of β-catenin.
CONCLUSIONS: Using miR-seq-based profiling in SF from the TghuTNF mouse model 
and validations in RA patient biopsies, the authors identified miR-221/222 and 
miR-323-3p as novel dysregulated miR in RA SF. Furthermore, the authors show 
that miR-323-3p is a positive regulator of WNT/cadherin signalling in RA SF 
suggesting its potential pathogenic involvement and future use as a therapeutic 
target in RA.