Presentation: Long Distance Migration of RASF: Role of Extracellular Matrix (2007)

1063 Long Distance Migration of RASF: Role of Extracellular Matrix

Background: Key players in rheumatoid arthritis (RA) pathophysiology are activated synovial fibroblasts (SF) which actively attach to, invade into and degrade cartilage which can be simulated in the SCID mouse model of RA. In preliminary experiments, we could show that RASF are able to migrate from a primary implantation site to a distant one, mainly via the blood stream. Therefore, the route of migration and the role of the extracellular matrix (ECM) were further analyzed in this study.
Methods: Healthy human cartilage was implanted into SCID mice together with RASF. At the contralateral flank, cartilage without cells was implanted. In addition, RASF were injected intravenously (iv), subcutaneously (sc) or intraperitoneally (ip) 14 days after cartilage implantation. To evaluate the role of the ECM towards the migratory behavior of RASF, complete RA synovium, bovine cartilage or necrotic cartilage, respectively, and contralaterally normal human cartilage were implanted. After 60 days, implants, organs, blood, murine ear cartilage and joints were removed. To detect human cells, species-specific immunohisto- and -cytochemistry were performed.
Results: RASF were not only able to invade and degrade cartilage which was inserted simultaneously with RASF, they also migrated to and invaded into the contralateral cartilage (Scores: inv 2.3±0.8 and 1.9±0.9, deg 1.8±0.8 and 1.6±0.6). Injection of cells led to strong destruction of the implanted cartilage, particularly after sc and iv application. Interestingly, implantation of complete synovial tissue, containing ECM and other cell types, led to migration of RASF to the contralateral cartilage in 5/11 animals (inv 2.0±1.0, deg 2.3±0.4). Single RASF were able to invade bovine and human necrotic cartilage and they could also be found in the murine ear and joint, but no invasion and degradation could be detected at day 60 after RASF application. Conclusions: RASF have the ability to migrate from a primary implant of cartilage or RA synovium to the contralateral implantation site via the blood stream and to mediate cartilage degradation. The cells are also able to cross the peritoneum after ip injection. Cartilage degradation appears to be independent of chondrocyte viability and of species background since RASF invade necrotic human as well as bovine cartilage. Therefore, the exposure to cartilage matrix, e. g. after microinjuries, may be sufficient for RASF to attach to the cartilage, to initiate destruction and spread RA from one joint to another.

 S. Lefèvre, None; A. Knedla, None; C. Tennie, None; I.H. Tarner, None; H. Stürz, None; J. Steinmeyer, None; S. Gay, None; U. Müller-Ladner, None; E. Neumann, None.