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Stromal cells like synovial fibroblasts gained great interest over the years, since it has become clear that they strongly influence their environment and neighbouring cells. The current review describes the role of synovial fibroblasts as cells of the innate immune system and expands on their involvement in inflammation and cartilage destruction in rheumatoid arthritis (RA). Furthermore, epigenetic changes in RA synovial fibroblasts and studies that focused on the identification of different subsets of synovial fibroblasts are discussed.

Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, or at all in some individuals, and cannot cure or prevent this disease. One major obstacle to developing better drugs is a lack of complete understanding of how inflammatory joint disease arises and progresses. Emerging evidence indicates an important role for the tissue microenvironment in the pathogenesis of RA. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix (ECM). These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a main site of disease activity in RA, positional and disease stage-specific cellular diversity exist. Improved understanding of the architecture of the synovium from gross anatomy to the single-cell level, in parallel with evidence demonstrating how the synovial ECM is vital for synovial homeostasis and how dysregulated signals from the ECM promote chronic inflammation and tissue destruction in the RA joint, has opened up new ways of thinking about the pathogenesis of RA. These new ideas provide novel therapeutic approaches for patients with difficult-to-treat disease and could also be used in disease prevention.Tissues are composed of cells and an extracellular matrix. In this Review, the authors discuss how a greater understanding of the role of the synovial extracellular matrix in rheumatoid arthritis could lead to improved disease diagnosis and new therapies.

NFκB activation and regulated cell death are important in tissue homeostasis, inflammation and pathogenesis. Here we show the role of the p55TNFR–IKK2l–Ripk3 axis in the regulation of synovial fibroblast homeostasis and pathogenesis in TNF-mediated mouse models of arthritis. Mesenchymal-specific p55TNFR triggering is indispensable for arthritis in acute and chronic TNF-dependent models. IKK2 in joint mesenchymal cells is necessary for the development of cartilage destruction and bone erosion; however, in its absence synovitis still develops. IKK2 deletion affects arthritic and antiapoptotic gene expression leading to hypersensitization of synovial fibroblasts to TNF/Ripk1-mediated death via district mechanisms, depending on acute or chronic TNF signals. Moreover, Ripk3 is dispensable for TNF-mediated arthritis, yet it is required for synovitis in mice with mesenchymal-specific IKK2 deletion. These results demonstrate that p55TNFR–IKK2–Ripk3 signalling orchestrates arthritogenic and death responses in synovial fibroblasts, suggesting that therapeutic manipulation of this pathway in arthritis may require combinatorial blockade of both IKK2 and Ripk3 signals. TNF is a major therapeutic target for rheumatoid arthritis (RA) and synovial fibroblasts are central to the pathogenesis of RA. Here the authors dissect TNF-induced death and activation signalling in RA synovial fibroblasts and TNF-driven arthritis and indicate that a successful therapeutic strategy might be to target both IKK2 and RIPK3 at the same time.

New analytical methods and the increasing availability of synovial biopsies have recently provided unprecedented insights into synovial activation in general and synovial fibroblast (SF) biology in particular. In the course of this development, SFs have become one of the most rapidly evolving and exciting fields of rheumatoid arthritis (RA) research. While their active role in the invasion of RA synovium into cartilage has long been studied, recent studies have brought new aspects of their heterogeneity and propagation in RA. This review integrates old and new evidence to give an overview picture of the processes active at the sites of invasive synovial tissue growth in RA.

A number of human diseases, such as arthritis and atherosclerosis, include characteristic pathology in specific anatomical locations. Here we show transcriptomic differences in synovial fibroblasts from different joint locations and that HOX gene signatures reflect the joint-specific origins of mouse and human synovial fibroblasts and synovial tissues. Alongside DNA methylation and histone modifications, bromodomain and extra-terminal reader proteins regulate joint-specific HOX gene expression. Anatomical transcriptional diversity translates into joint-specific synovial fibroblast phenotypes with distinct adhesive, proliferative, chemotactic and matrix-degrading characteristics and differential responsiveness to TNF, creating a unique microenvironment in each joint. These findings indicate that local stroma might control positional disease patterns not only in arthritis but in any disease with a prominent stromal component. Arthritis affects different joints variably despite systemic inflammatory cues. Here the authors show anatomical differences in the transcriptome, epigenome and function of synovial fibroblasts that might affect susceptibility to site-specific joint diseases.

DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.

ObjectiveTo investigate the effects of BET bromodomain protein inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts (RASF).MethodsThe expression of the BET bromodomain proteins BRD2, BRD3 and BRD4 was analysed in synovial tissue by immunohistochemistry. RASF were stimulated with tumour necrosis factor (TNF)-α, interleukin (IL)-1β and toll-like receptor (TLR) ligands (Pam3, pIC and lipopolysaccharide (LPS)) in the presence or absence of the BET inhibitor I-BET151, or siRNA targeting BRD2, BRD3 and BRD4. RASF expression of inflammatory mediators, including MMP1, MMP3, IL-6 and IL-8, was measured by q-PCR, q-PCR array and ELISA. Cellular viability, apoptosis, proliferation and chemoattractive properties of RASF were investigated using MTT, cell apoptosis ELISA, BrdU-based proliferation and transwell migration assays.ResultsBRD2, BRD3 and BRD4 proteins were detected in rheumatoid arthritis (RA) synovial tissue, expressed in both RASF and macrophages. I-BET151 suppressed cytokine and TLR ligand-induced secretion of MMP1, MMP3, IL-6 and IL-8, and mRNA expression of more than 70% of genes induced by TNF-α and IL-1β. Combined silencing of BRD2, BRD3 and BRD4 significantly reduced cytokine and TLR ligand-induced expression of a subset of gene products targeted by I-BET151, including MMP1, CXCL10 and CXCL11. I-BET151 treatment of RASF reduced RASF proliferation, and the chemotactic potential for peripheral blood leucocytes of RASF conditioned medium.ConclusionsInhibition of BET family proteins suppresses the inflammatory, matrix-degrading, proliferative and chemoattractive properties of RASF and suggests a therapeutic potential in the targeting of epigenetic reader proteins in RA.

Background Rheumatoid arthritis (RA) has a variable impact on different synovial joints, with inflammation being more commonly observed in some joints than others. Emerging evidence suggests that the anatomical variation in pathophysiology could result in differential responses to treatments across the joints, both within and between modes of action. This analysis aimed to characterize joint-specific responses to tofacitinib and methotrexate monotherapy in patients with RA. Methods This was a post hoc analysis of data from the phase III trial ORAL Start (NCT01039688), in methotrexate-naïve patients with RA. A paired joint pathology score (PJPS), derived from bilateral tender/swollen joint counts, was calculated. The percentage change from baseline in PJPS (%∆PJPS) and treatment-specific responses (tofacitinib 5 and 10 mg twice daily [BID] vs methotrexate; tofacitinib 5 vs 10 mg BID) for each patient joint pair, except for those with baseline/post-baseline PJPS = 0, were calculated at month 3, month 6, and month 12. Radiographic progression was similarly assessed using the Modified Total Sharp Score at month 6 and month 12. Results In methotrexate-naïve patients, differences in %∆PJPS demonstrated greater responses with tofacitinib vs methotrexate in most joint locations. Lesser responses with tofacitinib vs methotrexate were observed in most joints of the feet, particularly at month 12. Despite this, radiographic progression at month 12 was significantly worse in the foot (and metacarpophalangeal) joints of patients receiving methotrexate vs tofacitinib. Conclusion We observed variation in joint-specific responses with tofacitinib and methotrexate monotherapy. Despite a proximal–distal efficacy gradient, with better clinical responses in the feet, patients receiving methotrexate monotherapy demonstrated more radiographic progression in the foot joints compared with those receiving tofacitinib. These findings suggest that body site- and therapy-specific characteristics may interact to produce differential treatment responses. Trial registration ClinicalTrials.gov, NCT01039688.

Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. Results We identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Conclusion Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.