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Focal adhesion protein Lasp1 links the Arp2/3 complex to adherens junctions and promotes motility of arthritic fibroblast-like synoviocytes
  1. Denise Beckmann1,
  2. Annika Krause1,
  3. Uwe Hansen1,
  4. Hans P Kiener2,
  5. Thomas Karonitsch2,
  6. Stephan Blüml2,
  7. Joachim Kremerskothen3,
  8. Hermann Pavenstädt3,
  9. Thomas Pap1,
  10. Adelheid Korb-Pap1
  1. 1 Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany
  2. 2 Division of Rheumatology, Medical University of Vienna, Vienna, Austria
  3. 3 Department of Nephrology and Rheumatology, University Hospital of Muenster, Muenster, Germany
  1. Correspondence to Mrs Denise Beckmann, Institute of Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany; denise.beckmann{at}uni-muenster.de

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In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) undergo a stable transformation leading to an aggressive phenotype that mediates cartilage damage facilitated by increased expression of adhesion molecules. Actin-mediated cytoskeletal dynamics have gained increasing interest in the context of cellular responses and transformation, mostly in the context of cancer research. Recently, we have shown that the actin-binding LIM-and-SH3-domain-protein (Lasp1) in FLS from human patients with RA and arthritic mouse models such as hTNFtg mice1 exhibit similar changes in epigenetic regulation and results in its increased expression. In contrast, these changes could not be detected in healthy cells—both human and murine.2 In hTNFtg mice, Lasp1 deficiency led to significantly decreased cell migration and invasiveness and also strikingly malfunctional cell-to-cell contact formations in FLS caused by adherens junction (AJ) complex disruption. Cadherin-11 mediated cell-to-cell adhesion is a highly dynamic process and includes members of the catenin family such as β-catenin, α-catenin and p120ctn. In particular, β-catenin binding to Cadherin-11 is critical for its function in mediating cell-to-cell adhesion and cell rearrangements. The identification of the interaction of Lasp1 with β-catenin within Cadherin-11-based AJ has uncovered a new facet of Lasp1 functionality.2 It extends the role of Lasp1 beyond mere association with actin cytoskeleton organisation to include active involvement in the formation of FLS cell-to-cell contacts. Based on our previous data from humans and mouse data obtained from hTNFtg animals, the next approach was to determine whether Arp2/3, a key protein complex necessary for actin polymerisation, is part of the homotypic junction formation mediated by Lasp1 and components of the AJ complex or vice versa.3

To this end, we examined expression levels of Arp2 and Arp3 in lasp1-deficient FLS, also in the inflammatory hTNFtg background. Although both proteins were expressed, no differences in expression levels were observed …

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors DB designed and performed all experiments and wrote the manuscript, AK performed in vitro assays and WB, UH performed the transmission electron microscopy experiments, HPK contributed to the experimental design, TK and SB provided human samples and contributed to the experimental design, JK and HP made substantial contributions to data interpretation of in vitro experiments, TP and AK-P participated in all data analyses, directed the project and revised the manuscript.

  • Funding This study was funded by Deutsche Forschungsgemeinschaft (FOR2722-384170921/TP5 (AK-P)).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.