Osteopontin small interfering RNA protects mice from fulminant hepatitis

Yoshinari Saito, Shigeyuki Kon, Yukio Fujiwara, Yosuke Nakayama, Daisuke Kurotaki, Naoki Fukuda, Chiemi Kimura, Masashi Kanayama, Koyu Ito, Hongyan Diao, Yutaka Matsui, Yasuo Komatsu, Eiko Ohtsuka, Toshimitsu Uede

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1205-1214
Number of pages10
JournalHuman Gene Therapy
Volume18
Issue number12
DOIs
Publication statusPublished - 2007 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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