LAUSR

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. All tissues are made up of cells surrounded by an extracellular matrix (ECM), an intricate 3D molecular network that is an important determinant of tissue architecture and cell behaviour. The synovium is a complex anatomical tissue comprising many cell (sub)populations that are located in distinct sub-synovial niches, each of which are specialized to perform unique roles in synovial homeostasis. In rheumatoid arthritis (RA), infiltrating immune cells join tissue-resident cells, leading to qualitative changes in cell phenotype that promote inflammation and tissue destruction, and suppress the resolution of inflammation. The ECM has an important role in dictating the organization of synovial cell networks and in programming synovial cell specialization. Changes in the synovial microenvironment start to occur early in the development of RA, and these aberrant extracellular cues shape pathogenic cell behaviour during the onset and progression of disease. Analysing localized changes in the synovium can improve disease classification and patient stratification, and targeting the ECM holds promise for the development of new strategies to treat and prevent RA. All tissues are made up of cells surrounded by an extracellular matrix (ECM), an intricate 3D molecular network that is an important determinant of tissue architecture and cell behaviour. The synovium is a complex anatomical tissue comprising many cell (sub)populations that are located in distinct sub-synovial niches, each of which are specialized to perform unique roles in synovial homeostasis. In rheumatoid arthritis (RA), infiltrating immune cells join tissue-resident cells, leading to qualitative changes in cell phenotype that promote inflammation and tissue destruction, and suppress the resolution of inflammation. The ECM has an important role in dictating the organization of synovial cell networks and in programming synovial cell specialization. Changes in the synovial microenvironment start to occur early in the development of RA, and these aberrant extracellular cues shape pathogenic cell behaviour during the onset and progression of disease. Analysing localized changes in the synovium can improve disease classification and patient stratification, and targeting the ECM holds promise for the development of new strategies to treat and prevent RA.