@article{b75ecd2d4e1a4714a2e8d86f52381fe8,
title = "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 surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3–5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients—emanating from vascular endothelial cells outwards—in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.",
author = "{Accelerating Medicines Partnership Rheumatoid Arthritis & Systemic Lupus Erythematosus (AMP RA/SLE) Consortium} and Kevin Wei and Ilya Korsunsky and Marshall, {Jennifer L.} and Anqi Gao and Watts, {Gerald F.M.} and Triin Major and Croft, {Adam P.} and Jordan Watts and Blazar, {Philip E.} and Lange, {Jeffrey K.} and Thornhill, {Thomas S.} and Andrew Filer and Karim Raza and Donlin, {Laura T.} and Jennifer Albrecht and Anolik, {Jennifer H.} and William Apruzzese and Boyce, {Brendan F.} and Boyle, {David L.} and Bridges, {S. Louis} and Buckner, {Jane H.} and Bykerk, {Vivian P.} and Edward DiCarlo and James Dolan and Eisenhaure, {Thomas M.} and Firestein, {Gary S.} and Fonseka, {Chamith Y.} and Goodman, {Susan M.} and Gravallese, {Ellen M.} and Gregersen, {Peter K.} and Guthridge, {Joel M.} and Maria Gutierrez-Arcelus and Nir Hacohen and Holers, {V. Michael} and Hughes, {Laura B.} and Ivashkiv, {Lionel B.} and James, {Eddie A.} and James, {Judith A.} and Jonsson, {A. Helena} and Josh Keegan and Stephen Kelly and Lee, {Yvonne C.} and Lederer, {James A.} and Lieb, {David J.} and Mandelin, {Arthur M.} and McGeachy, {Mandy J.} and McNamara, {Michael A.} and Mears, {Joseph R.} and Nida Meednu and Harris Perlman",
note = "Funding Information: Acknowledgements This work was supported by R01 AR063709, R01 AR073833 and T32 AR007530-31 (to M.B.B.); R01 AR063759, U01 HG009379 and UH2 AR067677 (to S.R.); Rheumatology Research Foundation{\textquoteright}s Scientist Development Award (to K.W.); KL2 award (an appointed KL2 award) from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR002542) (to K.W.); and a Joint Biology Consortium Microgrant (to K.W.). M.B.B., S.R., I.K., J.L.M. and K.W. were funded as part of a collaborative research agreement with F. Hoffmann-La Roche Ltd (Basel, Switzerland). This report includes independent research supported by the National Institute for Health Research through the Birmingham Biomedical Research Center and Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, our funding bodies or the Department of Health. Funding was also provided by the Versus Arthritis RACE Rheumatoid Arthritis Pathogenesis Centre of Excellence (grant 20298) and Versus Arthritis Programme grant to C.D.B. and A.F. (grant 19791). A.P.C. was supported by a Wellcome Trust Clinical Career Development Fellowship no. WT104551MA. C.D.B. and T.M. are supported by funding from the Kennedy Trust for Rheumatology Research as part of the Arthritis Therapy Acceleration Programme. We thank the BWH Single Cell Genomics Core for assistance in scRNA-seq experiments. We thank members of the Brenner and Raychaudhuri laboratory for discussions. We acknowledge the University of Birmingham Medical School Imaging Suite and the assistance of R. Shaw. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = jun,
day = "11",
doi = "10.1038/s41586-020-2222-z",
language = "English (US)",
volume = "582",
pages = "259--264",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7811",
}