Rheumatoid arthritis (RA) is characterized by hyperplastic synovial pannus tissue, which mediates destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) are a key component of this invasive synovium and have a major role in the initiation and perpetuation of destructive joint inflammation. The pathogenic potential of FLS in RA stems from their ability to express immunomodulating cytokines and mediators as well as a wide array of adhesion molecule and matrix-modelling enzymes. FLS can be viewed as 'passive responders' to the immunoreactive process in RA, their activated phenotype reflecting the proinflammatory milieu. However, FLS from patients with RA also display unique aggressive features that are autonomous and vertically transmitted, and these cells can behave as primary promoters of inflammation. The molecular bases of this 'imprinted aggressor' phenotype are being clarified through genetic and epigenetic studies. The dual behaviour of FLS in RA suggests that FLS-directed therapies could become a complementary approach to immune-directed therapies in this disease. Pathophysiological characteristics of FLS in RA, as well as progress in targeting these cells, are reviewed in this manuscript.
Fibroblast-like synoviocytes (FLS), normally found in the synovial intimal lining of diarthrodial joints, display an aggressive, invasive phenotype in rheumatoid arthritis (RA) and participate in joint destruction
FLS from patients with RA promote inflammatory cell recruitment and activation, pannus angiogenesis, cartilage degradation, and bone erosion
The phenotype of FLS from patients with RA is partly a passive response to the inflammatory milieu in vivo, and partly an imprinted feature that persists when the cells are cultured in vitro
Imprinted anomalies of FLS in RA arise, at least in part, through epigenetic modifications of the genome, such as altered microRNA expression and DNA methylation
Increased knowledge of the biology of FLS in RA will pave the way to novel FLS-targeted therapies with limited immunosuppressive action
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The authors are indebted to M. Bottini and S. Stanford for help with preparation of the figures. This work was supported, in part, by Institutional La Jolla Institute of Allergy and Immunology funds (to N. Bottini) and by NIH grants R01AI067752, R01 AI070555, and R01 AR47825 (to G. S. Firestein). This manuscript is #1556 published from the La Jolla Institute of Allergy and Immunology.
The authors declare no competing financial interests.
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Bottini, N., Firestein, G. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat Rev Rheumatol 9, 24–33 (2013). https://doi.org/10.1038/nrrheum.2012.190
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