The orally-active and selective c-Fms tyrosine kinase inhibitor Ki20227 inhibits disease progression in a collagen-induced arthritis mouse model.
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.
Ohno
Hiroaki
H
Discovery Research Laboratories, Research Division, Kirin Pharma Co., Ltd., Gunma, Japan. h-ohno@kirin.co.jp
Uemura
Yasunori
Y
Murooka
Hideko
H
Takanashi
Hiromi
H
Tokieda
Takemi
T
Ohzeki
Yumiko
Y
Kubo
Kazuo
K
Serizawa
Isao
I
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology; D015153:Blotting, Western; D001842:Bone and Bones / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D018450:Disease Progression; D005434:Flow Cytometry; D007249:Inflammation / Q000188:drug therapy*; D016173:Macrophage Colony-Stimulating Factor / Q000187:drug effects; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D013154:Spleen / Q000187:drug effects; D013844:Thiazoles / Q000627:therapeutic use*
D016207:Cytokines; C517050:N-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-methoxyphenyl)-N'-(1-(1,3-thiazole-2-yl)ethyl)urea; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D016173:Macrophage Colony-Stimulating Factor