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The trans-endothelial migration of murine synovial fibroblasts of hTNF transgenic mice is controlled by JAM-C
  1. Marianne Heitzmann1,2,
  2. Adelheid Korb-Pap1,
  3. Christina Koers-Wunrau1,
  4. George Kollias3,
  5. Stefan Butz4,
  6. Dietmar Vestweber4,
  7. Hermann Pavenstädt2,
  8. Thomas Pap1
  1. 1Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster, Muenster, Germany
  2. 2Internal Medicine D, Department of Nephrology and Rheumatology, University Hospital Muenster, Muenster, Germany
  3. 3Institute of Immunology, Biomedical Sciences Research Center, Vari, Greece
  4. 4Max-Planck-Institute for Molecular Biomedicine, University of Muenster, Muenster, Germany

Abstract

Background and objectives Recent studies demonstrated the potential of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to migrate long distances via the bloodstream and invade distant cartilage in the SCID mouse model of disease.While the mechanisms of trans-endothelial migration of RA-FLS are largely unclear the junctional adhesion molecule C (JAM-C) has become of interest due to its involvement in trans-endothelial migration of leucocytes. Here, the authors used the hTNFtg mouse as a model for human RA and studied the role of JAM-C in the transmigration of FLS derived from these mice.

Materials and methods The expression of JAM-C on wild-type and hTNFtg FLS was investigated by western-blot analysis and immunocytochemistry. The transmigratory capacity of these cells was studied in a transmigration assay using murine endothelioma cells (bEnd.5) as an endothelial barrier and IL-1alpha treated murine cartilage tissue as chemoattractant stimulus. Functional analyses included the knock down of JAM-C expression by siRNA against murine JAM-C as well as its neutralisation by blocking antibodies.

Results The authors found the expression of JAM-C on the surface of both wild-type and hTNFtg FLS which is prominently located on sites of cell-cell interactions. Moreover, Western blot data revealed an elevated expression of JAM-C in FLS from hTNFtg mice. Transmigration experiments demonstrated a significantly higher potential of hTNFtg FLS to migrate through the endothelial monolayer than FLS from wild-type mice (+40%, p≤0,05), and cartilage explants pretreated with IL-1α enhanced the migratory capacity of hTNFtg FLS. Interestingly, siRNA-mediated knock down of JAM-C expression on hTNFtg FLS resulted in a reduction of transmigration of about 40% compared to mock control (p≤0,01). Likewise, the neutralisation of JAM-C by blocking antibodies against murine JAM-C reduced the number of transmigrated hTNFtg FLS on a similar level.

Conclusion Our data demonstrate that the inflammatory environment within the joints of hTNFtg mice induces an up-regulation of JAM-C on FLS, which is characteristic for human RA-FLS. Moreover, they indicate that this environment supports the development of a trans-migrating phenotype of FLS able to get through endothelial barriers. JAM-C seems to be involved functionally in the transmigration and, thus, in extravasation of FLS and, therefore targeting JAM-C may be a promising therapeutic strategy for RA.

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