Oral administration of recombinant adeno-associated virus-mediated bone morphogenetic protein-7 suppresses CCl(4)-induced hepatic fibrosis in mice

Mol Ther. 2012 Nov;20(11):2043-51. doi: 10.1038/mt.2012.148. Epub 2012 Jul 31.

Abstract

Fibrogenesis and hepatocyte degeneration are the main pathological processes in chronic liver diseases. Transforming growth factor-β1 (TGF-β1) is the key profibrotic cytokine in hepatic fibrosis. Bone morphogenetic protein-7 (BMP-7) is a potent antagonist of TGF-β1 and an antifibrotic factor. In this study, we generated a recombinant adeno-associated virus carrying BMP-7 (AAV-BMP-7) and tested its ability to suppress carbon tetrachloride (CCl(4))-induced hepatic fibrosis when orally administered to mice. Our results show that the ectopic expression of BMP-7 in gastrointestinal (GI) mucosa due to the AAV-BMP-7 administration led to the long-term elevation of serum BMP-7 concentrations and resulted in the drastic amelioration of CCl(4)-induced hepatic fibrosis in BALB/c mice. Immunostaining for α-smooth muscle actin (α-SMA) and desmin demonstrated that AAV-BMP-7 inhibited the activation of hepatic stellate cells (HSCs) in the fibrotic mouse liver. Moreover, the ectopic expression of BMP-7 promoted hepatocyte proliferation, as confirmed by an increase in the amount of proliferating cell nuclear antigen (PCNA)-positive hepatocytes in the mice that received AAV-BMP-7. Our results clearly indicate that BMP-7 is capable of inhibiting hepatic fibrosis and promoting hepatocyte regeneration. We suggest that oral AAV-BMP-7 could be developed into a safe, simple, and effective therapy for hepatic fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Administration, Oral
  • Animals
  • Bone Morphogenetic Protein 7 / biosynthesis
  • Bone Morphogenetic Protein 7 / blood
  • Bone Morphogenetic Protein 7 / genetics*
  • Cell Proliferation
  • Chemokine CCL4
  • Dependovirus / genetics*
  • Desmin / metabolism
  • Gastrointestinal Tract / metabolism
  • Gene Expression
  • Genetic Vectors / administration & dosage
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / physiology
  • Hyaluronic Acid / blood
  • Hydroxyproline / metabolism
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / therapy*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / blood
  • Recombinant Proteins / genetics

Substances

  • Actins
  • Bone Morphogenetic Protein 7
  • Chemokine CCL4
  • Desmin
  • Recombinant Proteins
  • bmp7 protein, mouse
  • Hyaluronic Acid
  • Hydroxyproline