Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes

Abstract

Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets. Fibroblast-like synoviocytes in rheumatoid arthritis have an aggressive phenotype caused, in part, by epigenetic imprinting, which contributes to various pathological processes. Understanding the mechanisms underlying the cell abnormalities and phenotypes, including their spatial and temporal differences, could lead to new therapies. Rheumatoid arthritis (RA) is a complex immune-mediated disease with clinical manifestations primarily involving synovial inflammation and joint damage. Fibroblast-like synoviocytes (FLS) contribute to the pathogenesis of RA and are epigenetically imprinted with an aggressive phenotype in RA. Synovial fibroblasts, including FLS, can have distinct phenotypes with different functional characteristics. Epigenetic mechanisms associated with FLS imprinting in RA include alterations in DNA methylation, histone modifications and microRNA expression. Integration of data from multi-omics analyses is needed to improve the characterization of FLS in RA. Therapies that target FLS are emerging as promising therapeutic tools, raising hope for future applications in RA.