Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis

Denise Beckmann, Anja Römer-Hillmann, Annika Krause, Uwe Hansen, Corinna Wehmeyer, Johanna Intemann, David J. J. Gorter, Berno Dankbar, Jan Hillen, Marianne Heitzmann, Isabell Begemann, Milos Galic, Toni Weinhage, Dirk Foell, Rizi Ai, Joachim Kremerskothen, Hans P. Kiener, Sylvia Müller, Thomas Kamradt, Christopher Schröder, Elsa Leitão, Bernhard Horsthemke, Philip Rosenstiel, Karl Nordström, Gilles Gasparoni, Nina Gasparoni, Jörn Walter, Na Li, Xinyi Yang, Ho-Ryun Chung, Hermann Pavenstädt, Nico Lindemann, Hans J. Schnittler, Wei Wang, Gary S. Firestein, Thomas Pap and Adelheid Korb-Pap ()
Additional contact information
Denise Beckmann: University Hospital Münster
Anja Römer-Hillmann: University Hospital Münster
Annika Krause: University Hospital Münster
Uwe Hansen: University Hospital Münster
Corinna Wehmeyer: University Hospital Münster
Johanna Intemann: University Hospital Münster
David J. J. Gorter: University Hospital Münster
Berno Dankbar: University Hospital Münster
Jan Hillen: University Hospital Münster
Marianne Heitzmann: University Hospital Münster
Isabell Begemann: University of Münster
Milos Galic: University of Münster
Toni Weinhage: University Children’s Hospital Münster
Dirk Foell: University Children’s Hospital Münster
Rizi Ai: 9500 Gilman Drive, UC San Diego
Joachim Kremerskothen: University Hospital Münster
Hans P. Kiener: Medical University of Vienna
Sylvia Müller: Jena University Hospital, Friedrich Schiller University
Thomas Kamradt: Jena University Hospital, Friedrich Schiller University
Christopher Schröder: University of Duisburg-Essen
Elsa Leitão: University Hospital of Essen, University of Duisburg-Essen
Bernhard Horsthemke: University Hospital of Essen, University of Duisburg-Essen
Philip Rosenstiel: University of Kiel
Karl Nordström: Saarland University
Gilles Gasparoni: Saarland University
Nina Gasparoni: Saarland University
Jörn Walter: Saarland University
Na Li: Otto-Warburg-Laboratories
Xinyi Yang: Otto-Warburg-Laboratories
Ho-Ryun Chung: Otto-Warburg-Laboratories
Hermann Pavenstädt: University Hospital Münster
Nico Lindemann: University of Münster
Hans J. Schnittler: University of Münster
Wei Wang: 9500 Gilman Drive, UC San Diego
Gary S. Firestein: Allergy and Immunology, 9500 Gilman Drive, UCSD School of Medicine
Thomas Pap: University Hospital Münster
Adelheid Korb-Pap: University Hospital Münster

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract The 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.

Date: 2021
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DOI: 10.1038/s41467-021-23706-8

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