Abstract
Rheumatoid arthritis is an immune-mediated inflammatory disease in which fibroblasts contribute to both joint damage and inflammation. Fibroblasts are a major cell constituent of the lining of the joint cavity called the synovial membrane. Under resting conditions, fibroblasts have an important role in maintaining joint homeostasis, producing extracellular matrix and joint lubricants. In contrast, during joint inflammation, fibroblasts contribute to disease pathology by producing pathogenic levels of inflammatory mediators that drive the recruitment and retention of inflammatory cells within the joint. Recent advances in single-cell profiling techniques have transformed our ability to examine fibroblast biology, leading to the identification of specific fibroblast subsets, defining a previously underappreciated heterogeneity of disease-associated fibroblast populations. These studies are challenging the previously held dogma that fibroblasts are homogeneous and are providing unique insights into their role in inflammatory joint pathology. In this review, we discuss the recent advances in our understanding of how fibroblast heterogeneity contributes to joint pathology in rheumatoid arthritis. Finally, we address how these insights could lead to the development of novel therapies that directly target selective populations of fibroblasts in the future.
Highlights
In this review, we highlight new approaches and applications of single-cell profiling techniques[1,2] and how these data are leading to unique insights into the phenotypic and functional heterogeneity of fibroblasts in the joint.[3]
|2 introduction of biological disease-modifying anti-rheumatic drugs targeting either leukocytes or their derived products has led to a step change in the management of RA, 30%- 40% of patients do not respond to such therapies, regardless of the mechanism of action of the drug used.8-13 These observations suggest the existence of additional pathways of disease persistence that remain to be identified and therapeutically targeted.[14]
We further demonstrated an expansion of immune effector fibroblasts expressing fibroblast activation protein-α (FAPα) and THY1 in the synovial tissue of individuals with RA, compared to patients with OA, consistent with previous studies demonstrating an expansion of sub-lining fibroblast subsets in RA.[38]
Summary
We highlight new approaches and applications of single-cell profiling techniques[1,2] and how these data are leading to unique insights into the phenotypic and functional heterogeneity of fibroblasts in the joint.[3].
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