Adenovirus-mediated expression of BMP-7 suppresses the development of liver fibrosis in rats

Abstract

Background: Liver cirrhosis, which is caused by the accumulation of extracellular matrix materials, is a serious clinical problem that can progress to hepatic failure. Transforming growth factor-b (TGFb) plays a pivotal role in extracellular matrix production, but bone morphogenetic protein (BMP)-7, a member of the TGFb superfamily, can antagonise the fibrogenic activity of TGFb. Aim: In this study, we examined whether adenovirus-mediated overexpression of BMP-7 (Ad-BMP-7) antagonised the effect of TGFb in vitro and in vivo. Methods and results: In primary cultured rat stellate cells and the LX-2 human stellate cell line, induction of BMP-7 by Ad-BMP-7 infection decreased the expression of collagen 1A2 mRNA and smooth muscle a-actin in the presence or absence of TGFb, via Smad 1/5/8 phosphorylation. BMP-7 triggered the mRNA expression of inhibitors of differentiation 2 (Id2) in LX-2. Although endogenous expression of BMP-7 was hardly detectable, Smad1 and Id2 overexpression increased BMP-7 expression in LX-2. A liver fibrosis model was induced by the repetitive intraperitoneal injection of thioacetamide (200 mg/kg body weight) twice per week for up to 7 weeks. In rats administered Ad-BMP-7 via the tail vein, hydroxyproline content and the areas stained by Sirius red dye in the liver were significantly reduced compared to controls. Ad-Id2 also reduced fibrosis.Conclusion: These data demonstrate that BMP-7, Smad 1/5/8 and Ids interact to antagonise hepatic fibrogenesis.

BMPS and Liver: More Questions than Answers

“…Upon BMP7 administration they observed a decrease in fibrotic lesions and improved liver function as determined by the analysis of albumin serum levels [122]. In the same line of evidence, it has been reported that adenovirus-mediated expression of BMP7 reduces liver fibrosis in rats, but the mechanism of this effect was not determined [123]. BMP7 protective properties in liver injuries have been also supported by evidence suggesting that endogenous BMP7 enhances regeneration of liver mass after partial hepatectomy being therefore a physiological regulator of hepatocyte proliferation and function [5].…”

Endoglin Differentially Modulates Antagonistic Transforming Growth Factor-β1 and BMP-7 Signaling

“…BMP-7 targets mesangial cells in kidney and hepatic stellate cells in liver that are key mediator cells during fibrogenesis. Moreover, it has been shown in both cell types that BMP-7 directly interferes with profibrogenic TGF-␤1 signaling (57,64). Because endoglin is also expressed by mesangial and hepatic stellate cells (43,65), it is tempting to speculate that endoglin is a critical modifier of fibrogenic responses.…”

“…In the light of fibrogenic processes, the finding that endoglin is a modifier of BMP-7 signaling is very interesting. In experimental models of kidney fibrosis and liver fibrosis, the administration of BMP-7 resulted in resolution of fibrosis (63,64). BMP-7 targets mesangial cells in kidney and hepatic stellate cells in liver that are key mediator cells during fibrogenesis.…”

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

“…Recent studies, however, have convincingly used components of either collagen ␣(1)I, collagen ␣2(I), or ␣-SMA promoters to direct transgene expression in activated stellate cells (311,312,367). More challenging has been the identification of transgenic promoters to ectopically express genes in quiescent stellate cells.…”