Fibroblast‐like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: Evidence of a link between an increased myofibroblast‐like phenotype and high‐inflammation synovitis

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Abstract
Objective Given the heterogeneity of gene expression patterns and cellular distribution between rheumatoid arthritis (RA) synovial tissues, we sought to determine whether this variability was also reflected at the level of the fibroblast‐like synoviocyte (FLS) cultured from RA synovial tissues. Methods Gene expression profiles in FLS cultured from synovial tissues obtained from 19 RA patients were analyzed using complementary DNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal components analysis. Genes that differed significantly in their expression between FLS cultures were selected using Statistical Analysis of Microarrays software. Real‐time quantitative polymerase chain reaction was performed to validate the microarray data. Immunocytochemistry was applied to study the expression of the genes of interest in FLS and synovial tissues. Results Hierarchical clustering identified 2 main groups of FLS characterized by distinctive gene expression profiles. FLS from high‐inflammation synovial tissues revealed increased expression of a transforming growth factor β/activin A–inducible gene profile that is characteristic of myofibroblasts, a cell type considered to be involved in wound healing, whereas increased production of growth factor (insulin‐like growth factor 2/insulin‐like growth factor binding protein 5) appeared to constitute a characteristic feature of FLS derived from low‐inflammation synovial tissues. The molecular feature that defines the myofibroblast‐like phenotype was reflected as an increased proportion of myofibroblast‐like cells in the heterogeneous FLS population. Myofibroblast‐like cells were also found upon immunohistochemical analysis of synovial tissue. Conclusion Our findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium.

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