title: Osteopontin small interfering RNA protects mice from fulminant hepatitis.
abstract: 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.
authors.affiliation: Research Section of Molecular Pathogenesis, Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Saito
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurotaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Fukuda
authors.forename: Chiemi
authors.initials: C
authors.lastname: Kimura
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanayama
authors.forename: Koyu
authors.initials: K
authors.lastname: Ito
authors.forename: Hongyan
authors.initials: H
authors.lastname: Diao
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsui
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Eiko
authors.initials: E
authors.lastname: Ohtsuka
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: 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
chemical_list: D034741:RNA, Small Interfering; C506896:Spp1 protein, mouse; D053495:Osteopontin; D003208:Concanavalin A