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

The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model

Hiroaki Ohno  1 , Yasunori Uemura, Hideko Murooka, Hiromi Takanashi, Takemi Tokieda, Yumiko Ohzeki, Kazuo Kubo, Isao Serizawa
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Free article

The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model

Hiroaki Ohno et al. Eur J Immunol. 2008 Jan.
Free article

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.

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