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

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 beta- 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.

• Authors: Fumitaka Terabe, Masayasu Kitano, Mari Kawai, Yusuke Kuwahara, Toru Hirano, Junsuke Arimitsu, Keisuke Hagihara, Yoshihito Shima, Masashi Narazaki, Toshio Tanaka, Ichiro Kawase, Hajime Sano, Atsushi Ogata
• Journal: Modern rheumatology (Mod Rheumatol) Vol. 19 Issue 5 Pg. 522-9 ( 2009) ISSN: 1439-7609 [Electronic] England
• PMID: 19568828 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Piperazines
• Platelet-Derived Growth Factor
• Pyrimidines
• Imatinib Mesylate
• Freund's Adjuvant
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Arthritis, Experimental (chemically induced, drug therapy, metabolism)
• Benzamides
• Blotting, Western
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Fibroblasts (drug effects, metabolism)
• Freund's Adjuvant (toxicity)
• Humans
• Imatinib Mesylate
• Phosphorylation (drug effects)
• Piperazines (administration & dosage)
• Platelet-Derived Growth Factor (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (administration & dosage)
• Rats
• Signal Transduction (drug effects)
• Synovial Membrane (cytology, drug effects, metabolism)