Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis

Autor: Rizi Ai, Uwe Hansen, Johanna Intemann, Elsa Leitão, Toni Weinhage, Isabell Begemann, Joachim Kremerskothen, Anja Römer-Hillmann, Ho-Ryun Chung, Marianne Heitzmann, Thomas Pap, Hermann Pavenstädt, Hans P. Kiener, Na Li, Annika Krause, Wei Wang, Gilles Gasparoni, Berno Dankbar, Sylvia Müller, Corinna Wehmeyer, Denise Beckmann, Dirk Foell, Philip Rosenstiel, Bernhard Horsthemke, Thomas Kamradt, Adelheid Korb-Pap, Karl Nordström, Hans Schnittler, David J. J. de Gorter, Nico Lindemann, Jörn Walter, Gary S. Firestein, Xinyi Yang, Nina Gasparoni, Christopher Schröder, Jan Hillen, Milos Galic
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
medicine.medical_treatment
Inflammatory arthritis
Medizin
General Physics and Astronomy
Arthritis
Arthritis
Rheumatoid
Mice
0302 clinical medicine
Neoplasms
beta Catenin
Cytoskeleton
Mice
Knockout
Multidisciplinary
Synovial Membrane
Adherens Junctions
LIM Domain Proteins
Cadherins
Cell Transformation
Neoplastic
Phenotype
Tumor necrosis factor alpha
Female
musculoskeletal diseases
Genetically modified mouse
Science
Biology
General Biochemistry
Genetics and Molecular Biology
Article
Adherens junction
03 medical and health sciences
medicine
Animals
Humans
Cell migration
Rheumatoid arthritis
Adaptor Proteins
Signal Transducing
Homeodomain Proteins
Osteoblasts
Growth factor
General Chemistry
Fibroblasts
medicine.disease
Mice
Inbred C57BL
Destructive Arthritis
Cytoskeletal Proteins
030104 developmental biology
Cancer cell
Cancer research
030217 neurology & neurosurgery
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021)
ISSN: 2041-1723
Popis: 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.
Databáze: OpenAIRE
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