Therapy of fibroblast-induced cartilage destruction in a novel SCID mouse model.

U Sack, MD, a, A Hirth, MSc a, U Anderegg, PhD b, K Wiedemeier a, B Funke a, J Richter a, F Krahnert a, F Emmrich, PhD a, J Lehmann, PhD c

a Institute of Clinical Immunology, University of Leipzig, Leipzig, Germany b Department of Dermatology, University of Leipzig, Leipzig, Germany c Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Germany

AIM Synovial membrane fibroblasts are considered to be a crucial cell population for joint destruction as well as disease progression in rheumatoid arthritis. Rheumatoid synovial fibroblast-like cells are able to induce destruction of cartilage and bone in SCID mice (hu/mu SCID arthritis). We have isolated a murine destructive fibroblastoid cell line and have established thereby a cartilage destruction model. METHODS A murine fibroblast cell line (LS48) was established. Cells were examined for morphology, surface molecules, cytokine secretion, and functional parameters. Cartilage destruction was induced by injection into SCID mouse knee joints. Disease process was modified by immunosuppressive drugs such as Cyclosporine A, Methotrexate, FK 506, and by gene therapy based on transfection with interleukins IL-4, -11, -12, and -15. Finally, morphology of cartilage destruction was investigated by histology. RESULTS Cell line LS48 was shown to exhibit characteristics of a fibroblast-like cell. Capability to secrete interleukin-6 but only few tumor necrosis factor revealed similarities to human invasive fibroblasts. A rapid progressive cartilage destruction within 10 days was induced by injection of 0.5 million cells into murine knees. Histology revealed invasion of fibroblast-like cells into the cartilage. Destruction could be reduced by Methotrexate but not Cyclosporine A or FK 504. CONCLUSION Cartilage destruction as induced by intraarticular application of murine fibroblast like cell line LS48, is a rapid and highly reproducible model for investigation of invasive processes driven by fibroblast-like cells. The process can be modulated by antirheumatic drugs and by IL-11, whereas IL-4 caused aggravation of the process and IL-12 and IL-15 did not reveal visible effects. The model of LS48-driven cartilage destruction provides the opportunity to investigate processes and new therapeutic strategies for diseases with joint destruction in an easy-to-handle animal model.

KEY WORDS: immunosuppression, gene therapy.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Autoimmunity.