Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Nature communications 2021-06, Vol.12 (1), p.3624-17, Article 3624
Hauptverfasser: Beckmann, Denise, Römer-Hillmann, Anja, Krause, Annika, Hansen, Uwe, Wehmeyer, Corinna, Intemann, Johanna, de Gorter, David J. J., Dankbar, Berno, Hillen, Jan, Heitzmann, Marianne, Begemann, Isabell, Galic, Milos, Weinhage, Toni, Foell, Dirk, Ai, Rizi, Kremerskothen, Joachim, Kiener, Hans P., Müller, Sylvia, Kamradt, Thomas, Schröder, Christopher, Leitão, Elsa, Horsthemke, Bernhard, Rosenstiel, Philip, Nordström, Karl, Gasparoni, Gilles, Gasparoni, Nina, Walter, Jörn, Li, Na, Yang, Xinyi, Chung, Ho-Ryun, Pavenstädt, Hermann, Lindemann, Nico, Schnittler, Hans J., Wang, Wei, Firestein, Gary S., Pap, Thomas, Korb-Pap, Adelheid
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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. Fibroblast-like synoviocytes are important mediators of joint pathology in rheumatoid arthritis (RA). Here the authors show that Lasp1 is epigenetically regulated and highly expressed by these cells in RA and its deletion can limit joint pathology in a mouse model of inflammatory arthritis.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-23706-8