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Inhibition of c-kit tyrosine kinase by imatinib mesylate induces apoptosis in mast cells in rheumatoid synovia: a potential approach to the treatment of arthritis

A Juurikivi^1,*, C Sandler^1,*, K A Lindstedt², P T Kovanen², T Juutilainen³, M J Leskinen², T Mäki¹, K K Eklund¹

¹ Department of Medicine, Division of Rheumatology, Helsinki University Central Hospital, Helsinki, Finland
² Wihuri Research Institute, Helsinki, Finland
³ Department of Orthopaedic Surgery, Helsinki University Central Hospital, Helsinki, Finland

Correspondence to:
Correspondence to:
Dr K K Eklund
Division of Rheumatology, Helsinki University Central Hospital, Kasarmikatu 11–13, 00130 Helsinki, Finland; kari.eklund{at}HUS.fi

Background: Mast cells have been implicated in the pathogenesis of arthritis, but elucidation of their precise role has been hampered by a lack of efficient and selective inhibitors of their function.

Objective: To elucidate the role of mast cells in the pathogenesis of rheumatoid arthritis (RA) and to assess whether apoptosis of cultured and synovial tissue mast cells can be induced by inhibiting mast cell growth factor receptor, c-kit tyrosine kinase.

Methods and results: Double staining with tumour necrosis factor (TNF) and tryptase antibodies showed the presence of TNF positive mast cells in human rheumatoid synovial tissue. Selective activation of mast cells by anti-IgE resulted in production of TNF in synovial tissue cultures. Inhibition of the c-kit tyrosine kinase with imatinib mesylate (1.0–10 µmol/l) induced profound apoptosis in cultured mast cells as judged by typical apoptotic morphology, increased number of apoptotic nucleosomes, and activation of caspases 8 and 9. Importantly, imatinib also induced apoptosis of mast cells in explant cultures of synovial tissue obtained from patients with RA as judged by a TUNEL assay. Inhibition of c-kit tyrosine kinase was accompanied by significant reduction of TNF production in synovial tissue cultures.

Conclusion: Mast cells may have a role in the pathogenesis of RA, and inhibition of c-kit may be a new means of inhibiting mast cell activity and of abrogating the contribution of mast cells to synovial inflammation in RA.

Abbreviations: ELISA, enzyme linked immunosorbent assay; FCS, fetal calf serum; HuMC, human mast cells; IL, interleukin; mBMMC, mouse bone marrow derived mast cells; PDGF, platelet derived growth factor; RA, rheumatoid arthritis; SCF, stem cell factor; TNF, tumour necrosis factor; WCM, WEHI-conditioned media

Keywords: rheumatoid arthritis; mast cells; c-kit tyrosine kinase

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