OBJECTIVE:

Aberrant activation of synovial fibroblasts (SFs) is a key determinant in the pathogenesis of rheumatoid arthritis (RA). We aimed to produce a map of gene expression and epigenetic changes occurring in this cell type during disease progression in the human TNF-transgenic model of arthritis, and identify commonalities with human SFs.

METHODS:

We used deep sequencing to probe the transcriptome, the methylome and the chromatin landscape of cultured mouse arthritogenic SFs at three stages of disease, as well as SFs stimulated with human TNF. We performed bioinformatics analyses at the gene, pathway and network levels, compared mouse and human data, and validated selected genes in both species.

RESULTS:

We report that SF arthritogenicity is reflected on distinct dynamic patterns of transcriptional deregulation, enriched in pathways of the innate immune response and mesenchymal differentiation. A functionally-representative subset of these changes is associated with methylation, mostly in gene bodies. The arthritogenic state involves highly active promoters, marked by H3K4 trimethylation. There is significant overlap between mouse and human data, at the level of deregulated genes and to an even higher extent at the level of pathways.

CONCLUSION:

This work presents the first systematic examination of the pathogenic changes that occur in mouse synovial fibroblasts in progressive TNF-driven arthritogenesis. Significant correlations with respective human RA SF data further validate the human TNF-transgenic mouse as a reliable model of the human disease. The resource of data generated here may serve as a framework for the discovery of novel pathogenic mechanisms and disease biomarkers.