Oral Administration of Recombinant Adeno-associated Virus-mediated Bone Morphogenetic Protein-7 Suppresses CCl(4)-induced Hepatic Fibrosis in Mice

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2012 Aug 2

PMID 22850680

Citations 23

Authors

Zhi-Ming Hao

Min Cai

Yi-Fei Lv

Yan-Hua Huang

Hong-Hong Li

Affiliations

Soon will be listed here.

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.

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