Vol.19 No.5

Original Article

Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway

Authors

Fumitaka Terabe1 , Masayasu Kitano2 , Mari Kawai1 , Yusuke Kuwahara1 , Toru Hirano1 , Junsuke Arimitsu1 , Keisuke Hagihara1 , Yoshihito Shima1 , Masashi Narazaki1 , Toshio Tanaka1 , Ichiro Kawase2 , Hajime Sano2, Atsushi Ogata1

  • Department of Respiratory Medicine, Allergy and Rheumatic Disease, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita Osaka, 565-0871, Japan
  • Division of Rheumatology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
Received:

25 September 2008

Accepted:

18 May 2009

Published online:

1 July 2009

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Abstract

Overgrowth of the synovium plays an important role in the pathogenesis of rheumatoid arthritis (RA). Platelet-derived growth factor (PDGF) is one of the most potent mitogenic factors of synovial cells, and imatinib mesylate (imatinib) is a specific inhibitor of the PDGF receptor tyrosine kinase. The aim of this study was to elucidate the anti-rheumatic activity of imatinib. The in vivo effects of imatinib were assessed by evaluating the sequential manifestation of adjuvant-induced arthritis in rats using paw volume and clinical scores. Imatinib was found to inhibit rat adjuvant-induced arthritis, but the inhibitory effects were incomplete. To confirm the mechanism of anti-rheumatic-activity of imatinib, we assessed the in vitro effects of imatinib on the proliferation of RA synovial fibroblast-like cells (RASFs) using a MTT assay. Intracellular signaling of PDGF was evaluated by Western blot analysis. Platelet-derived growth factor was found to induce a significant proliferation of RASFs, while imatinib inhibited PDGF-induced proliferation of RASF. Imatinib also inhibited PDGF-induced phosphorylation of the PDGF receptor and Akt, whereas constitutive activated extracellular signal-regulated kinase was not inhibited by imatinib. In contrast, imatinib did not inhibit transforming growth factor β- and basic fibroblast growth factor-induced proliferation of RASF. Oral administration of imatinib ameliorated adjuvant-induced arthritis in rats, and it inhibited PDGF-induced RASF proliferation through disruption of the PDGF-R to Akt kinase signaling pathway. Because imatinib cannot inhibit the non-PDGF-dependent proliferation of RASFs, the anti-rheumatic effect of imatinib may be incomplete. The development of inhibitors of RASF proliferation may lead to the successful treatment of RA.

Key words

Imatinib - PDGF - Rheumatoid arthritis