Background/Purpose: Fibroblasts are key effector cells in the persistence of synovial inflammation and joint damage. It is not yet known whether specific subsets of synovial fibroblasts exist, and if so, if they are responsible for the distinct fibroblast mediated features observed in inflammatory arthritis such as invasion of cartilage, bone damage, and persistence of inflammation. Using selective cell deletion strategies and adoptive cellular transfer we demonstrate the presence of functionally distinct subsets of synovial fibroblasts that mediate specific aspects of joint pathology.

Methods: Flow cytometry of digested synovial tissue was performed to determine the expression of fibroblast subsets using a cassette of distinct cell surface makers. Bulk transcriptomics was performed using ultra-low input RNAseq. We utilized a transgenic mouse in which FAP expressing cells were conditionally ablated (FAP-DTR) by administration of diphtheria toxin. Poly-arthritis was performed using either the KRN serum transfer model. Mice were scored for clinical signs of arthritis and MicroCT was performed to evaluate inflammatory bone changes.

Results:

We identified distinct populations of fibroblasts defined by their expression of a cassette of cell surface markers including: podoplanin (PDPN), fibroblast activation protein (FAP), VCAM-1, Cadherin-11 and Thy1.2. Bulk transcriptomic analysis of these targeted subpopulations of cells revealed distinct transcriptional signatures which associated with whether the fibroblast subsets were located in the lining or sub-lining layers of the synovium. Synovial inflammation was associated with activation and selective expansion of these cell subsets with distinct compartments of the synovial membrane. Within the intimal layer of the synovium FAP+ PDPN+ Thy 1- fibroblasts highly express MMPs, proteases and were found within pannus tissue invading articular cartilage and bone. In contrast, PDPN+ FAP+ Thy1+, cells rapidly expand within the sub-intimal layer and express pro-inflammatory cytokines, chemokine and survival factors associated with the recruitment and retention of leucocytes.

Utilising their shared expression of FAP we selectively deleted these cells using the FAP-DTR mouse. The deletion of these cells in vivo lead to attenuation of synovial inflammation, inhibited leucocyte accumulation and protected against inflammatory bone damage and remodelling. Consistent with these findings the adoptive transfer of FAP+, PDPN+ Thy1+ cells into arthric mouse joints lead to a more severe and persistent inflammatory arthritis, ehereas injection of FAP+ PDPN+ Thy1- cells did not.

Conclusion: Synovial inflammation is associated with the expansion, activation and differentiation of fibroblasts into pathogenic distinct functional subsets of cells that regulate those specific aspects of inflammatory joint pathology. Direct targeting of specific pathogenic subsets of synovial fibroblasts may provide a novel, non-immunosuppressive approach to the treatment of inflammatory arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/functionally-distinct-pathogenic-subsets-of-fibroblasts-exist-within-the-inflamed-synovial-membrane-and-mediate-specific-aspects-of-inflammatory-disease-pathology/