The Orally-Active and Selective c-Fms Tyrosine Kinase Inhibitor Ki20227 Inhibits Disease Progression in a Collagen-Induced Arthritis Mouse Model

Eur J Immunol. 2008 Jan;38(1):283-91. doi: 10.1002/eji.200737199.

Abstract

Macrophage colony-stimulating factor (M-CSF) is important in the development of macrophages and osteoclasts. Previous studies have also shown that CD11b(+) myeloblasts and osteoclasts play key roles during inflammation and bone destruction in arthritic lesions. In this study, we investigated whether N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]-2-methoxyphenyl}-N'-[1-(1,3-thiazole-2-yl)ethyl] urea (Ki20227), an inhibitor of the M-CSF receptor (c-Fms), suppressed disease progression in a type II collagen (CII)-induced arthritis (CIA) mouse model. We found that Ki20227 inhibited M-CSF-dependent reactions, such as lipopolysaccharide-induced tumor necrosis factor-alpha production, which were enhanced by M-CSF in vitro. Oral administration of Ki20227 in vivo prevented inflammatory cell infiltration and bone destruction, and consequently suppressed disease progression. In addition, the number of CD11b(+), Gr-1(+), and Ly-6G(+) cells in the spleen decreased in the Ki20227-treated mice, and the CII-induced cytokine production in splenocytes isolated from the Ki20227-treated arthritic mice was also reduced. These observations indicate that Ki20227 might exert its therapeutic effects in the CIA mouse model by suppressing the M-CSF-dependent accumulation of both inflammatory and osteoclast cells, as well as by inhibiting inflammatory cytokine production. Hence, inhibitors of the c-Fms tyrosine kinase might act as anti-inflammatory or anti-osteolytic agents against arthritis.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / immunology
  • Blotting, Western
  • Bone and Bones / drug effects
  • Cytokines / biosynthesis
  • Cytokines / drug effects
  • Disease Progression
  • Flow Cytometry
  • Inflammation / drug therapy*
  • Macrophage Colony-Stimulating Factor / drug effects
  • Male
  • Mice
  • Osteoclasts / drug effects
  • Phenylurea Compounds / therapeutic use*
  • Protein Kinase Inhibitors / therapeutic use*
  • Spleen / drug effects
  • Thiazoles / therapeutic use*

Substances

  • Cytokines
  • N-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-methoxyphenyl)-N'-(1-(1,3-thiazole-2-yl)ethyl)urea
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Thiazoles
  • Macrophage Colony-Stimulating Factor