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Effects of a novel tyrosine kinase inhibitor in rheumatoid arthritis synovial fibroblasts
  1. Lars C Huber (lars.huber{at}usz.ch)
  1. Center of Experimental Rheumatology, University Hospital Zurich, Switzerland
    1. Peter Künzler (peter.kuenzler{at}usz.ch)
    1. Center of Experimental Rheumatology, University Hospital Zurich, Switzerland
      1. Susan H Boyce (susan.h.boyce{at}gsk.com)
      1. GlaxoSmithKline, Medicines Research Center, Stevenage, United Kingdom
        1. Beat A Michel (beat.michel{at}usz.ch)
        1. Center of Experimental Rheumatology, University Hospital Zurich, Switzerland
          1. Renate E Gay (renate.gay{at}usz.ch)
          1. Center of Experimental Rheumatology, University Hospital Zurich, Switzerland
            1. Barbara S Ink (barbara.ink{at}roche.com)
            1. GlaxoSmithKline, Medicines Research Center, Stevenage, United Kingdom
              1. Steffen Gay (steffen.gay{at}usz.ch)
              1. Center of Experimental Rheumatology, University Hospital Zurich, Switzerland

                Abstract

                Objective: Biologicals have revolutionized the treatment of rheumatoid arthritis (RA). Still, progressive joint destruction can be observed in many patients and the search for novel molecular therapies targeting specific signaling pathways is going on. In the present study we investigated the effects of GW282974, a novel compound directed against tyrosine kinase activity with respect to the potential suppression of inflammation and destruction.

                Methods: Synovial tissue specimens were obtained from RA patients undergoing surgical joint replacement. Rheumatoid arthritis synovial fibroblasts (RASFs) were stimulated with cytokines and GW282974 was added in different concentrations. Gene expression was checked by TaqMan PCR, using 18S as housekeeping gene. Protein analysis was quantified by ELISA. Cell growth and proliferation was measured using the ‘ViaLight’ proliferation assay.

                Results: EGF had no effect on the gene expression profile of RASFs when used as single stimulatory agent. In combination with pro-inflammatory mediators however, EGF showed a synergistic effect. The expression of matrix metalloproteinases, inflammatory cytokines and cyclooxygenase-2 on mRNA level was strongly increased, whereas the addition of GW282974 abrogated these effects in a dose-dependent manner. These data could be confirmed on protein/ lipid levels analysing the supernatants of RASFs by ELISA. Similarly, cell growth and proliferation of RASFs were inhibited by GW282974 in a dose- and time-dependent manner. On the other hand, no cytotoxic effects were seen within the concentrations used.

                Discussion: GW282974 appears to interfere with both the inflammatory and the destructive pathway in RASFs and might be used as novel therapeutic strategy for the treatment of RA.

                • rheumatoid arthritis
                • synovial fibroblasts
                • tyrosine kinase

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