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Review
, 9 (1), 24-33

Duality of Fibroblast-Like Synoviocytes in RA: Passive Responders and Imprinted Aggressors

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Review

Duality of Fibroblast-Like Synoviocytes in RA: Passive Responders and Imprinted Aggressors

Nunzio Bottini et al. Nat Rev Rheumatol.

Abstract

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.

Figures

Figure 1
Figure 1
Roles of FLS in RA. FLS play a critical part in many pathogenic events in the RA synovium. They can contribute to pathology through a reduced ability to undergo apoptosis (forming pannus), the production of proteases that degrade the extracellular matrix, and invasion into cartilage. In addition, FLS produce a variety of molecules that modulate growth, inflammation, angiogenesis, and cell recruitment, and induce activation of and cytokine production by immune cells. Abbreviations: CCL2, CC-chemokine ligand 2; CXCL10, CXC-chemokine ligand 10; FLS, fibroblast-like synoviocytes; GM-CSF, granulocyte-macrophage colony-stimulating factor; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; RA, rheumatoid arthritis; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor.
Figure 2
Figure 2
Molecular pathology of FLS in RA. Upward and downward arrows indicate changed functional levels of the corresponding protein in RA FLS (cultured FLS derived from patients with RA) versus osteoarthritis and/or normal FLS. a | Enhanced MAPK signalling increases production of MMPs and cytokines in RA. The JNK pathway is shown; analogous cascades in the ERK and p38 MAPK pathways are not shown. Ligation of surface receptors activates the MAPK pathway, leading to phosphorylation of JNKs and increased expression of genes such as MMP genes. JNKs are hyperactive in RA FLS, whereas GADD45β expression is reduced; SRC and RAF activity are increased, which further contributes to JNK activation. b | Activation of the NFκB pathway is increased in RA FLS. Stimulation of surface receptors increases IKKβ activation, leading to degradation of IκB. Nuclear translocation of NFκB leads to transcription of proinflammatory genes. Increased activation of NFκB activity in RA is promoted, in part, by overexpression of PI3K and/or decreased expression of PTEN in the RA synovium. c | Damage to key regulators including mitochondrial genes and p53 underlies the reduced tendency of RA FLS to undergo apoptosis. Increased activation and/or expression of c-FLIP and Bcl-2 and altered sumoylation contribute to enhanced survival of RA FLS. Abbreviations: Bcl-2, apoptosis regulator Bcl-2; c-FLIP, cellular FLICE-like inhibitory protein; ERK, extracellular signal-regulated kinase; FASL, FAS ligand; FLS, fibroblast-like synoviocytes; GADD45β, growth arrest and DNA damage-inducible protein GADD45β; IκB, inhibitor of NFκB; IKKβ, IκB kinase β; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MKK7, MAPK kinase 7; MMP, matrix metalloproteinase; NFκB, nuclear factor κB; p53, cellular tumour antigen p53; PI3K, phosphoinositide 3-kinase; PTEN, phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase; PUMA, p53 upregulated modulator of apoptosis; RAF, RAF proto-oncogene serine/threonine-protein kinase; SRC, proto-oncogene tyrosine-protein kinase Src; TAK1, transforming growth factor β-activated kinase 1; TLR, Toll-like receptor.
Figure 3
Figure 3
Imprinted anomalies of RA FLS (cultured FLS derived from patients with RA). a | Somatic mutations might promote the aggressive characteristics and proliferation of FLS in RA. Inflammatory injury (e.g. from ROS or RNS) is thought to induce an imbalance in the expression of DNA repair proteins, decreasing levels of MSH6, which protects against point mutations, and simultaneously increasing expression of MSH3, which protects against large genomic rearrangements. Further mutations can result, and somatic mutations are inherited by daughter cells. b | Epigenetic modifications of FLS that contribute to pathology in RA can be inherited or induced by environmental factors. Aberrant patterns of histone acetylation alter gene expression in RA FLS; histone methylation and phosphorylation are additional epigenetic mechanisms that have not yet been thoroughly investigated in RA FLS. Altered expression of miRNA can contribute to the aggressive phenotype of RA FLS. Differential DNA methylation leads to altered expression of key genes involved in cell adhesion, cytokine production and proliferation. Abbreviations: FLS, fibroblast-like synoviocytes; HDAC, histone deacetylase; MSH6, DNA mismatch repair protein MSH6; MSH3, DNA mismatch repair protein MSH3; miRNA, microRNA; RA, rheumatoid arthritis; RNS, reactive nitrogen species; ROS, reactive oxygen species.

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