The molecular pathogenesis of rheumatoid arthritis (RA) is still poorly understood. Given the heterogeneity in gene expression patterns and cellular distribution between RA synovial tissue, we determined whether this variability is also reflected at the level of fibroblast-like synoviocytes (FLS) cultured from those synovial tissues.
Gene expression profiles in FLS from 19 RA synovial tissues were analyzed using cDNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal component analysis. Genes that differed significantly in expression between FLS cultures were selected using statistical analysis of microarrays. Real-time PCR was performed to validate microarray data. Immunostaining was applied to study the expression of the genes of interest in FLS and synovial tissues.
Hierarchical clustering identified two main groups of FLS characterized by distinctive gene expression profiles. FLS from high inflammatory synovial tissues revealed increased expression of a transforming growth factor beta/ Activin A inducible gene program that is characteristic of myofibroblasts, a cell type that is considered to be involved in wound healing, whereas increased growth factor (IGF2/IGFBP5) production appears to constitute a characteristic feature of FLS derived of low inflammatory synovial tissues. The molecular feature that defines the myofibroblast-like phenotype is reflected as an increased proportion of myofibroblast-like cells in the heterogeneous FLS population. Myofibroblast-like cells are also found upon immunohistochemical analysis of synovial tissue.
The data support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence for a possible link between FLS behavior and the inflammatory status of RA synovium.