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Reduction of cartilage destruction in a rapid progressive arthritis model in SCID mice

Fibroblasts are considered to be a crucial cell population for disease progression, as well as joint destruction in rheumatoid arthritis. Recent data underline the potency of rheumatoid synovial fibroblast-like cells to induce the destruction of cartilage and bone, e.g. following intra-articular injection into SCID mice. We have isolated a fibroblastoid cell line by co-cultivation of human rheumatoid fibroblasts with murine fibroblasts. The generated cell line exhibits characteristics of rheumatoid fibroblasts and genetic alterations indicating a transformed phenotype. These cells have been shown to induce a rapid destruction of articular cartilage following intra-articular instillation. Fibroblastoid cells (LS48) were examined for cytogenetic characteristics, morphology, surface molecules, cytokine secretion, and functional parameters. 500,000 cells were injected directly into SCID mouse knee joints to induce cartilage destruction. Mice were monitored for joint swelling, serological parameters and by radiological methods. Furthermore, the effects of immunosuppressive drugs such as cyclosporine A, methotrexate, and FK 506 were investigated in this model. In addition, transfection of LS48 was performed with IL-11 as well as IL-15 prior to arthritis induction to investigate influence on cartilage destruction. Finally, the histology of cartilage destruction was explored. LS48 shows characteristics of a fibroblast-like cell but is of murine origin. Secretion of matrix metalloproteinases 3,9 and 13 as well of inter-leukine-6 and tumor necrosis factor revealed similarities to human invasive rheumatoid synovial membrane fibroblasts. Rapid progressive cartilage destruction within 10 days was induced by instillation into SCID mouse knee joints. Morphology revealed invasion of fibroblast-like cells into the articular cartilage. Destruction could be reduced by methotrexate but not by cyclosporineA or FK506, indicating a fibroblast-directed action of methotrexate connected to reduction of joint destruction in RA patients. Transfection with cytokines did not act on cartilage destruction, but IL-11 reduced apoptosis of chondrocytes. Induction of cartilage destruction by intra-articular application of murine fibroblast-like cells, in particular LS48, is a rapid and highly reproducible model for investigating invasive arthritis and can be modulated by drugs or gene transfer. This provides the opportunity to check novel therapeutic strategies for the treatment of arthritis, especially focussing on the reduction of cartilage erosion.

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Sack, U., Hirth, A., Funke, B. et al. Reduction of cartilage destruction in a rapid progressive arthritis model in SCID mice. Arthritis Res Ther 4 (Suppl 1), 105 (2002).

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