Osteopontin small interfering RNA protects mice from fulminant hepatitis.
Osteopontin (OPN) has been implicated in various helper T cell type 1 immunity-mediated diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), Crohn's disease, and fulminant hepatitis. Increased expression of OPN has been detected in pathological foci of these diseases. RA and fulminant hepatitis have been successfully treated by administration of neutralizing anti-OPN antibody in mice. Antibody treatment may elicit side effects including allergic reactions against heterologous antibody proteins, thus necessitating humanization of antibody. To provide alternative means to neutralize OPN function, in this study we explored the possibility of using OPN small interfering RNA (siRNA) to silence OPN gene expression. In vitro, OPN siRNA efficiently silenced the expression of both exogenous and endogenous OPN gene. After hydrodynamic intravenous injection of OPN siRNA, OPN siRNA was efficiently delivered to the liver, which resulted in the efficient silencing of OPN gene expression in liver. In a murine model of concanavalin A (ConA)-induced fulminant hepatitis, OPN expression was elevated in liver and severe hepatic necrosis was induced. Importantly, after OPN siRNA treatment, the OPN expression level in liver was significantly reduced and liver tissue injury was ameliorated, as reflected by the significant reduction of serum alanine aminotransferase levels and almost normal liver histology. Thus, this study indicates that OPN siRNA delivery has therapeutic potential in various inflammatory diseases in which OPN play a critical role by silencing OPN gene expression in vivo.
Saito
Yoshinari
Y
Research Section of Molecular Pathogenesis, Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Kon
Shigeyuki
S
Fujiwara
Yukio
Y
Nakayama
Yosuke
Y
Kurotaki
Daisuke
D
Fukuda
Naoki
N
Kimura
Chiemi
C
Kanayama
Masashi
M
Ito
Koyu
K
Diao
Hongyan
H
Matsui
Yutaka
Y
Komatsu
Yasuo
Y
Ohtsuka
Eiko
E
Uede
Toshimitsu
T
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D003208:Concanavalin A / Q000633:toxicity; D015316:Genetic Therapy / Q000379:methods*; D008099:Liver / Q000737:chemistry; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D014162:Transfection
D034741:RNA, Small Interfering; C506896:Spp1 protein, mouse; D053495:Osteopontin; D003208:Concanavalin A