Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis
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Published:2021-06-15
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Beckmann Denise, Römer-Hillmann Anja, Krause Annika, Hansen Uwe, Wehmeyer Corinna, Intemann Johanna, de Gorter David J. J.ORCID, Dankbar Berno, Hillen Jan, Heitzmann MarianneORCID, Begemann Isabell, Galic MilosORCID, Weinhage Toni, Foell DirkORCID, Ai Rizi, Kremerskothen Joachim, Kiener Hans P., Müller Sylvia, Kamradt Thomas, Schröder Christopher, Leitão ElsaORCID, Horsthemke BernhardORCID, Rosenstiel Philip, Nordström KarlORCID, Gasparoni GillesORCID, Gasparoni Nina, Walter JörnORCID, Li Na, Yang XinyiORCID, Chung Ho-Ryun, Pavenstädt Hermann, Lindemann Nico, Schnittler Hans J.ORCID, Wang Wei, Firestein Gary S.ORCID, Pap ThomasORCID, Korb-Pap AdelheidORCID
Abstract
AbstractThe LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/β-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.
Funder
Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference51 articles.
1. Pap, T. & Korb-Pap, A. Cartilage damage in osteoarthritis and rheumatoid arthritis-two unequal siblings. Nat. Rev. Rheumatol. 11, 606–615 (2015). 2. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003). 3. Korb-Pap, A., Bertrand, J., Sherwood, J. & Pap, T. Stable activation of fibroblasts in rheumatic arthritis-causes and consequences. Rheumatol. 55, ii64–ii67 (2016). 4. Lefevre, S. et al. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009). 5. Bottini, N. & Firestein, G. S. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. 9, 24–33 (2013).
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