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

Nature Reviews Rheumatology volume 16, pages 316–333 (2020)Cite this article

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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.

Key points

  • 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.

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Fig. 1: The synovial joint in health and in RA.
Fig. 2: Genetic and epigenetic mechanisms involved in FLS imprinting in RA.
Fig. 3: Diversity of FLS in RA.
Fig. 4: The hallmark features of FLS in RA.

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  1. Division of Rheumatology, Allergy and Immunology, University of California San Diego School of Medicine, San Diego, CA, USA

    Gyrid Nygaard & Gary S. Firestein

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Glossary terms

RNA sequencing

(RNA-seq). A technique that measures the quantity and sequences of RNA in a biological sample, using next-generation sequencing.

Transposable elements

DNA sequences that can move (transpose) to a new position in the genome, which can affect the activity of nearby genes.

Enhancer

Short sequences of regulatory DNA elements that, when bound by transcription factors, can promote transcription of a particular gene by enhancing the activity of the gene promoter through physical interactions in cis.

Whole-genome bisulfite sequencing

A technique for assessing genome-wide DNA methylation, using sodium bisulfite treatment and DNA sequencing.

Assay for transposase-accessible chromatin using sequencing

A technique that identifies areas of open chromatin in the genome that are accessible to transcription factors, using a transposase and DNA sequencing.

Chromatin immunoprecipitation sequencing

A technique that identifies the DNA binding sites in the genome for a particular protein of interest, using antibodies and DNA sequencing.

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Nygaard, G., Firestein, G.S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat Rev Rheumatol 16, 316–333 (2020). https://doi.org/10.1038/s41584-020-0413-5

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