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A6.7 The junctional adhesion molecule JAM-3 regulates the motility of fibroblast-like synoviocytes
  1. U König1,
  2. M Heitzmann1,
  3. D Beckmann1,
  4. J Hillen1,
  5. U Hansen1,
  6. U Saunders2,
  7. C Hartmann3,
  8. A Korb-Pap1,
  9. T Pap1
  1. 1University Hospital Muenster, Institute of Experimental Musculoskeletal Medicine, University of Muenster, Germany
  2. 2University of Muenster, Internal Medicine D, Department of Nephrology and Rheumatology, Muenster, Germany
  3. 3Institute of Experimental Musculoskeletal Medicine, Dept. Bone and Skeletal Research, University of Muenster, Germany

Abstract

Background and objectives Rheumatoid arthritis (RA) is a disease of a continuous activation and expansion of the synovium involving migration and dissemination of fibroblast-like synoviocytes (FLS). Several lines of evidence indicate that adhesion molecules play a crucial role in this process. We have focused on the junctional adhesion molecule 3 (JAM-3), known to be involved in adhesion, polarity and migration of other cells. So far it has been demonstrated that blocking of JAM-3 in a serum transfer model of RA ameliorates the disease. However, the question of whether JAM-3 is involved in fibroblast motility or primarily regulates the influx of inflammatory cells remains unknown. Therefore, our objective was to clarify the involvement of JAM-3 in the establishment of cell-cell and cell-matrix contacts as well as in the migration of FLS.

Materials and methods As an arthritis model we use human TNFalpha transgenic (hTNFtg) mice that due to high levels of human TNFalpha develop a RA-like disease. FLS form these animals as well as form JAM-3 floxed mice CreERT2 (tamoxifen inducible cre line) and control mice were isolated by collagenase digestion of the hind paws. Cells were subjected to electrical cell-substrate impedance sensing (ECIS) surface staining (FACS), immunofluorescence, in vitro cell migration assays and standard molecular biology methods.

Results JAM-3 was found on both wild type and hTNFtg synoviocytes. Blocking or silencing of JAM-3 significantly increased cell spreading in an modified scratch assay but decreased migration in an in vitro transmigration assay, indicating that JAM-3 is involved in the establishment of cell-cell contacts between FLS. In line with this notion ECIS experiments revealed altered adhesion properties of these cells. Explaining these findings, we found that JAM-3 co-localises with the tight junction molecule zo-1 at cell contact sites, which are connected to actin cell filaments. The ultrastructure of these structures and an influence of Jam-3 on the cytoskeleton dynamics is under investigation.

Conclusions JAM-3 modulates migration of FLS in vitro, which may contribute to the beneficial effects of JAM-3 inhibition as seen in the serum transfer model of RA in vivo. We suggest that Jam-3 is an adhesion molecule, responsible for controlling motility by organising the cytoskeleton in FLS.

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