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SAT0050 A novel function of junctional adhesion molecule-C in regulation of trans-endothelial migration of murine synovial fibroblasts
  1. M. Heitzmann1,
  2. A. Korb-Pap1,
  3. C. Wunrau1,
  4. G. Kollias2,
  5. S. Butz3,
  6. D. Vestweber3,
  7. H. Pavenstädt4,
  8. T. Pap1
  1. 1Institute of Experimental Muskuloskeletal Medicine, University Hospital Muenster, Muenster, Germany
  2. 2Institute of Immunology, Biomedical Sciences Research Center, Vari, Greece
  3. 3Max-Planck-Institute for Molecular Biomedicine, University Muenster
  4. 4Internal Medicine D, University Hospital Muenster, Muenster, Germany


Background Recent studies demonstrated the potential of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to emigrate from affected joints and migrate via the bloodstream toward distant healthy cartilage in the SCID mouse model of disease. While the mechanisms of breaking endothelial barriers by RA-FLS are largely unclear, the junctional adhesion molecule C (JAM-C) has become of interest in this context due to its involvement in trans-endothelial migration of leukocytes. Using the human TNF transgenic (hTNFtg) mouse as a model for human RA, we studied the role of JAM-C in the transmigration of FLS derived from these mice.

Methods The expression pattern of JAM-C on wild-type and hTNFtg FLS was analyzed by Western-blot and immunocytochemistry. We investigated the transmigratory capacity of these cells in a transmigration assay using murine endothelioma cells (bEnd.5) as an endothelial barrier, IL-1alpha treated murine cartilage tissue served as chemoattractant stimulus within this setting. Functional analyses included the knock down of JAM-C expression by siRNA against murine JAM-C as well as its neutralization by blocking antibodies.

Results The expression of JAM-C could be detected on the surface of both wild-type and hTNFtg FLS and it was primarly located on sites of cell-cell interactions. Additionally, Western blot data showed an elevated expression of JAM-C in FLS from hTNFtg mice. Our transmigration experiments demonstrated a markedly higher potential of hTNFtg FLS to migrate through the endothelial monolayer than FLS from wild-type mice (+40%, p≤0.05), and cartilage explants pre-treated with IL-1alpha as chemoattractant strengthened the migratory capacity of hTNFtg FLS. Interestingly, knock down of JAM-C expression on hTNFtg FLS mediated by siRNA decreased the number of transmigrated cells of about 40% comparing with mock control (p≤0.01). Equally, the neutralization of JAM-C by blocking antibodies against murine JAM-C resulted in a reduction of transmigration on a similar level.

Conclusions The inflammatory environment characteristic for joints of hTNFtg mice induces an up-regulation of JAM-C on FLS similar to that of human FLS during RA. Moreover, the differentiation of a trans-migrating phenotype of FLS, capable to break through endothelial barriers is supported by this environment. In this context, JAM-C seems to be contributed to this process of transmigration and, thus, to the extravasation of FLS and, therefore targeting JAM-C may be a promising therapeutic strategy for RA.

Disclosure of Interest None Declared

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