Study: Synovial fibroblast positional identity controlled by inductive Notch signaling underlies pathologic damage in inflammatory arthritis 60056 cells

The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint. Recently, we found that a subset of fibroblasts undergo major expansion in RA and is linked to disease activity. However, the mechanism by which these fibroblasts expand and whether they are required for inflammation and pathology in RA is unknown. Here, we identified a critical role for Notch3 signaling in the differentiation of perivascular CD90(THY1)+ sublining fibroblasts. Using single cell RNA-sequencing and mixed cell micromass organoids, we found that Notch3 signaling drives both a transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, Notch3 and Notch target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of Notch3 attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal pathway underlies inflammation and pathology in inflammatory arthritis.