Nature. Notch3 is a key receptor for the differentiation and pathological development of rheumatoid arthritis fission membrane fibroblasts.

Synovial is a kind of mesenchymal tissue around the joint, which is mainly composed of fibroblasts, including the inner layer (LL) and the sublining layer (SL).in rheumatoid arthritis, synovial tissue hyperplasia, inflammation, invasion and destruction of the joint [1].recent studies have shown that in rheumatoid arthritis, a part of fibroblasts in the subinner layer expand and participate in the disease process [2].however, the molecular mechanism of differentiation and expansion of these fibroblasts is still unclear.recently, the team of soumya raychaudhuri and Michael Brenner of Harvard Medical School published a research paper entitled "Notch signaling drives synovial fibroblast identity and arthritis pathway" in nature.in this paper, the authors determined that Notch3 signaling plays a key role in the differentiation of perivascular and subinner fibroblasts expressing THY1.using single cell RNA sequencing (scrna SEQ) and synovial tissue like organs, we found that Notch3 signal drives transcription of fibroblasts and spatial gradient distribution from vascular endothelial cells outward.in active rheumatoid arthritis, Notch3 and Notch target genes were significantly up-regulated in synovial fibroblasts.in mice, knockout of Notch3 gene or use of antibodies to block Notch3 signal can alleviate inflammation and prevent joint injury caused by inflammatory arthritis.these results suggest that the positional identity of synovial fibroblasts is regulated by Notch signal from endothelial cells, and this signal interaction between stroma is the source of inflammation and pathological basis of inflammatory arthritis.the function of a tissue depends on its structural design. The core concept of this design is cellular zonation, which can reflect the division of labor among cells.previously, it has been reported that there is a corresponding relationship between the transcription gradient of scrna SEQ and the characteristics of cell location in tissues and organs such as brain and intestine [3].in this paper, the authors used scrna SEQ to determine the transcriptional gradient and cellular location in synovial tissue.Fig. 1. Scrna SEQ shows the location characteristics of fibroblasts, which play a key role in regulating lymph node and cancer immune response.in rheumatoid arthritis, synovial fibroblasts have long been regarded as promising therapeutic targets.however, there is no approved treatment for synovial fibroblasts.the location of fibroblasts in the endothelial system is determined by the authors. and further through the analysis of scrna SEQ data, we will focus on the Notch signaling pathway. Notch3, as a highly selective receptor of Notch signaling pathway in synovial fibroblasts, naturally becomes the most likely target. Fig. 2. Notch signaling pathway determines the location characteristics of synovial fibroblasts. The authors found that Notch3 signaling contributes to the differentiation of mural cells and subinner layer fibroblasts expressing THY1, which is necessary for the development of inflammatory arthritis. the expression of Notch3 in mouse synovium was detected by scrna SEQ, and it was confirmed that Notch3 was limited to parietal cells and fibroblasts, which was consistent with the increase of Notch receptor activation in perivascular cells. The Notch signal activity score of these cells in arthritis state was significantly higher than that in normal state. when the serum of K / BxN mice in severe arthritis model was injected into normal mice, the symptoms of arthritis and swelling were obvious, but when the serum was injected into Notch3 knockout mice, the symptoms were obviously weaker. in addition, the treatment of mice with anti-nrr3 twice a week also significantly reduced the symptoms of arthritis and swelling. in addition, anti-nrr3 treatment significantly reduced bone erosion. Fig. 3. The role of Notch3 inhibition in the differentiation of parietal cells from endothelial cells of inflammatory arthritis has been studied in the tissues of developing organs. on the basis of the relationship between Notch signal and pathogenesis of rheumatoid arthritis, the author's findings emphasize the importance and versatility of Notch signal in the process of pathological tissue remodeling [4]. Although previous studies focused on the interaction between Notch1 Signaling and cytokine activation in fibroblasts, this study further deepened the understanding of Notch signaling in rheumatoid arthritis by identifying Notch3 as a key receptor in the differentiation and pathological expansion of synovial fibroblasts in rheumatoid arthritis. these results suggest that targeted therapy for rheumatoid arthritis can be achieved by regulating Notch3 signaling in stromal cells. original link: plate maker: xiaoxianzi, Ref. 1. Dakin SG, Coles m, Sherlock JP, powrie F, Carr AJ, Buckley CD. Pathetic systemic cells as thermal targets in joint inflammation. Nat Rev rheumatol. 2018; 14 (12): 714 – 726 doi:10.1038/s41584-018-0112-72. Croft AP, Campos J, Jansen K, et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature. 2019; 570(7760): 246–251. doi:10.1038/s41586-019-1263-73. Vanlandewijck M, He L, Mäe MA, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018; 554(7693): 475–480. doi:10.1038/nature257394. Gao W, McCormick J, Connolly M, Balogh E, Veale DJ, Fearon U. Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis. Ann Rheum Dis. 2015; 74(6): 1275–1283. doi:10.1136/annrheumdis-2013-204105.