Notch signalling drives synovial fibroblast identity and arthritis pathology

Abstract

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 1 , 2 . Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity 3 , 4 , 5 . However, the molecular mechanism by which these fibroblasts differentiate and expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90( THY1 )+ fibroblasts. Using single cell RNA-sequencing and synovial tissue organoids, we found that NOTCH3 signaling drives both 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 signaling 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 crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

Bone Angiogenesis and Vascular Niche Remodeling in Stress, Aging, and Diseases

“…This fibroblast subpopulation is significantly upregulated in RA patients, localizing and expanding near the blood vessels and secreting proinflammatory cytokines (Mizoguchi et al, 2018). Upregulation of NOTCH3 and Notch target genes via blood vessels is found in active RA (Wei et al, 2020; Figure 3 and Table 1). Deletion of Notch3 or blocking of NOTCH3 signaling blocks fibroblast expansion, alleviates inflammation and prevents damage of inflamed joints, indicating a critical role for Notch3 signaling in regulating synovial fibroblast differentiation, expansion and disease activity (Wei et al, 2020).…”

Insights Into the Molecular Mechanism of Deer Antler Extract Serving as a Potential Chondroprotective Agent for Articular Cartilage

“…Rbp7, a family member of the cellular retinol-binding proteins, is signi cantly upregulated in osteoarthritic chondrocytes [69]. Notch3 is a family member of Notch receptors, and genetic deletion of Notch3 or the blockade of Notch3 signaling prevents joint damage and attenuates in ammation of in ammatory arthritis [70].…”

Investigating the molecular control of deer antler extract on articular cartilage 

“…Rbp7, a family member of the cellular retinol-binding proteins, is signi cantly upregulated in osteoarthritic chondrocytes [71]. Notch3 is a family member of Notch receptors, and genetic deletion of Notch3 or the blockade of Notch3 signaling prevents joint damage and attenuates in ammation of in ammatory arthritis [72]. (a chloride intracellular channel protein) are reported to be highly expressed under osteoarthritic condition [86][87][88][89][90][91][92][93][94][95].…”