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

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 ␤/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.Rheumatoid arthritis (RA) is a chronic inflammatory joint disease of unknown etiology that affects the

Expression of a pathogen-response program in peripheral blood cells defines a subgroup of Rheumatoid Arthritis patients

“…35 Although our current analysis supports the suggestion that an infectious agent is involved in the development of arthritis, the study design does not allow for a firm conclusion to be drawn. Formally we cannot exclude the possibility that the pathogen-response signature may have been triggered by endogenous danger signals that are released during inflammation, independent of infectious agents, such as heat shock proteins and DNA or RNA from damaged or dying cells.…”

Inhibition of forkhead box class O family member transcription factors in rheumatoid synovial tissue

“…Patients with RA with high phosphorylation levels of FoxO family members appear to represent a distinct subset of patients displaying low disease activity, as assessed by the ESR and CRP level. Interestingly, we have previously noted a similar correlation between disease activity and mRNA expression of insulin-like growth factor 1, which targets PI 3-kinase signaling pathways (26,27).…”

CCL21 Expression Pattern of Human Secondary Lymphoid Organ Stroma Is Conserved in Inflammatory Lesions with Lymphoid Neogenesis

“…Consistent with this, increased myofibroblast conversion has been reported in synovial fibroblasts derived from high-inflammation tis-sues in association to high expression of T cell/B cell and antigen-presenting cell genes. 55 Further ultrastructural studies are required to understand the actual competence of SMA ϩ fibroblastoid cells to organize functional networks and mediate antigen and chemokine delivery in human inflammatory ELTs.…”