Editors' ChoiceARTHRITIS

Inflammation or damage: Fibroblasts decide

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaax9562
DOI: 10.1126/scitranslmed.aax9562

Abstract

Functionally distinct fibroblast subsets mediate inflammation or tissue damage in inflammatory arthritis.

Tissue resident mesenchymal cells, including fibroblasts, exhibit disease and site-specific phenotypes, which can become epigenetically imprinted after exposure to inflammatory signals. Fibroblasts are implicated in the pathology of inflammatory joint disease; however, it has remained unclear whether all their purported functions, such as inflammation, fibrosis, and damage, occur in all fibroblasts or are restricted to discrete fibroblast subsets. Advancing understanding of the diversity and biology of fibroblast subsets presents an opportunity to develop precision therapeutic targeting of cells driving pathology in inflammatory arthritis.

Using murine models of inflammatory arthritis and synovial biopsies from patients with osteoarthritis or resolving and persistent rheumatoid arthritis (RA), Croft and colleagues identify and describe the biology of distinct fibroblast subsets responsible for mediating either inflammation or destruction of joint tissues. The authors found that fibroblast activation protein–α (FAPα), a surface glycoprotein expressed by activated fibroblasts, was abundant in synovial tissues and fibroblasts isolated from patients with persistent compared to resolving RA. A model of serum transfer–induced arthritis in a transgenic FAPα luciferase-DTR reporter mouse showed FAPα expression was localized to bone and cartilage, correlating with the severity of joint swelling. Subsequent deletion of FAPα-expressing fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis.

Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPα+ population. These included FAPα+THY1+ immune effector fibroblasts located in the synovial sublining, and FAPα+THY1 destructive fibroblasts present only in the synovial lining. Adoptive transfer of FAPα+THY1 fibroblasts into murine joints selectively mediated bone and cartilage damage with little impact on inflammation. In contrast, transfer of FAPα+THY1+ fibroblasts induced severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. These findings have so far been limited to murine models, but they have considerable translational implications, informing the development of new cell-based therapies to modulate inflammation and damage in patients with both inflammatory and degenerative forms of arthritis.

Future studies are required to determine whether FAPα+THY1 fibroblasts are present in greater numbers in the synovial lining layer of osteoarthritis compared with RA patients, as predicted from these findings. For now, researchers will be able to make advances toward new clinical strategies targeting pathogenic fibroblasts by inducing phenotypic conversion, selective depletion or replacement of these important cell types via epigenetic modification, monoclonal antibody–based cell depletion, and cell-based therapies.

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