Abstract

Fibroblast-like synoviocytes (FLS) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness, contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells, however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biological retinoid, which is a candidate drug for many diseases, but that has reached clinical use only for a few. Here, we explored the effect of all-trans retinoic acid (ATRA) on the aggressive phenotype of FLS from RA patients. RA FLS were treated with all-trans retinoic acid (ATRA), TNF or TNF+ATRA and cell migration and invasion were analysed. In addition, a microarray analysis of expression, followed by gene-set analysis and qPCR validation was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that were accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors.