TY - JOUR
T1 - Osteopontin small interfering RNA protects mice from fulminant hepatitis
AU - Saito, Yoshinari
AU - Kon, Shigeyuki
AU - Fujiwara, Yukio
AU - Nakayama, Yosuke
AU - Kurotaki, Daisuke
AU - Fukuda, Naoki
AU - Kimura, Chiemi
AU - Kanayama, Masashi
AU - Ito, Koyu
AU - Diao, Hongyan
AU - Matsui, Yutaka
AU - Komatsu, Yasuo
AU - Ohtsuka, Eiko
AU - Uede, Toshimitsu
PY - 2007/12/1
Y1 - 2007/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=37149012973&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=37149012973&partnerID=8YFLogxK
U2 - 10.1089/hum.2007.069
DO - 10.1089/hum.2007.069
M3 - Article
C2 - 17988193
AN - SCOPUS:37149012973
VL - 18
SP - 1205
EP - 1214
JO - Human Gene Therapy
JF - Human Gene Therapy
SN - 1043-0342
IS - 12
ER -