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Basic and translational research
Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts
  1. Elena Neumann1,
  2. Maria C Schwarz1,
  3. Rebecca Hasseli1,
  4. Marie-Lisa Hülser1,
  5. Simon Classen2,
  6. Michael Sauerbier3,
  7. Stefan Rehart4,
  8. Ulf Mueller-Ladner1
  1. 1 Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus-Liebig University Giessen, Bad Nauheim, Germany
  2. 2 Division of Vascular Surgery, Harvey-Vascular-Healthcare Center, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany
  3. 3 Department of Plastic, Hand and reconstructive Surgery, BGU Frankfurt, Frankfurt, Germany
  4. 4 Department of Orthopaedics and Trauma Surgery, Agaplesion Markus Hospital, Frankfurt, Germany
  1. Correspondence to Dr Elena Neumann, Internal Medicine and Rheumatology, Justus-Liebig-University Gießen, Bad Nauheim 61231, Germany; e.neumann{at}kerckhoff-klinik.de

Abstract

Tetraspanins function as membrane adaptors altering cell-cell fusion, antigen presentation, receptor-mediated signal transduction and cell motility via interaction with membrane proteins including other tetraspanins and adhesion molecules such as integrins. CD82 is expressed in several malignant cells and well described as tumour metastasis suppressor. Rheumatoid arthritis (RA) is based on persistent synovial inflammation and joint destruction driven to a large extent by transformed-appearing activated synovial fibroblasts (SF) with an increased migratory potential.

Objective CD82 is upregulated in RA synovial fibroblasts (RASF) compared with osteoarthritis (OA) SF as well as within RA compared with OA synovial lining layer (LL) and the role of CD82 in RASF was evaluated.

Methods CD82 and integrin immunofluorescence was performed. Lentiviral CD82 overexpression and siRNA-mediated knockdown was confirmed (realtime-PCR, Western blot, immunocytochemistry). RASF migration (Boyden chamber, scrape assay), attachment towards plastic/Matrigel, RASF-binding to endothelial cells (EC) and CD82 expression during long-term invasion in the SCID-mouse-model were evaluated.

Results CD82 was induced by proinflammatory stimuli in SF. In RA-synovium, CD82 was expressed in RASF close to blood vessels, LL, sites of cartilage invasion and colocalised with distinct integrins involved in tumour metastasis suppression but also in RA-synovium by RASF. CD82 overexpression led to reduced RASF migration, cell-matrix and RASF-EC adhesion. Reduced CD82 expression (observed in the sublining) increased RASF migration and matrix adhesion whereas RASF-EC-interaction was reduced. In SCID mice, the presence of CD82 on cartilage-invading RASF was confirmed.

Conclusion CD82 could contribute to RASF migration to sites of inflammation and tissue damage, where CD82 keeps aggressive RASF on site.

  • rheumatoid arthritis
  • fibroblasts
  • inflammation

https://doi.org/10.1136/annrheumdis-2018-212954

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors Project conception and design: EN, MSc, UM-L. Acquisition of data: MSc, RH, M-LH, MSa, SR. Analysis and interpretation of data: EN, MSc, M-LH, SC. Drafting and/or revision of article: EN, MSc, M-LH, UM-L.

    • Funding This project was funded by the Kerckhoff-Stiftung, the DFG excellence cluster for cardiopulmonary research (ECCPS) and the BMBF (IMPAM, project 01EC1008G).

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval Local ethics committee.

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

    • Data sharing statement There are no shared additional unpublished data from the study available.