Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis.

Jung Il Lee,Jocelyn H Wright,Kimberly J Riehle,Sebastian Yuen,Jean S Campbell,Kristina Sorg,Lananh Nguyen,Renay L Bauer,Brian J Hayes,Melissa M Johnson

doi:10.1152/ajpcell.00423.2014

Abstract

Chronic liver injury leads to fibrosis and cirrhosis. Cirrhosis, the end stage of chronic liver disease, is a leading cause of death worldwide and increases the risk of developing hepatocellular carcinoma. Currently, there is a lack of effective antifibrotic therapies to treat fibrosis and cirrhosis. Development of antifibrotic therapies requires an in-depth understanding of the cellular and molecular mechanisms involved in inflammation and fibrosis after hepatic injury. Two growth factor signaling pathways that regulate liver fibrosis are transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF). However, their specific contributions to fibrogenesis are not well understood. Using a genetic model of liver fibrosis, we investigated whether the canonical TGFβ signaling pathway was necessary for fibrogenesis. PDGF-C transgenic (PDGF-C Tg) mice were intercrossed with mice that lack Smad3, and molecular and histological fibrosis was analyzed. PDGF-C Tg mice that also lacked Smad3 had less fibrosis and improved liver lobule architecture. Loss of Smad3 also reduced expression of collagen genes, which were induced by PDGF-C, but not the expression of genes frequently associated with hepatic stellate cell (HSC) activation. In vitro HSCs isolated from Smad3-null mice proliferated more slowly than cells from wild-type mice. Taken together, these findings indicate that PDGF-C activates TGFβ/Smad3 signaling pathways to regulate HSC proliferation, collagen production and ultimately fibrosis. In summary, these results suggest that inhibition of both PDGF and TGFβ signaling pathways may be required to effectively attenuate fibrogenesis in patients with chronic liver disease.

Highlights

CHRONIC LIVER INJURY results in liver fibrosis, which may progress to cirrhosis [31, 42, 45], increasing the risk of developing hepatocellular carcinoma (HCC) [52]
We have previously reported that hepatic overexpression of platelet-derived growth factor (PDGF)-C results in progressive liver fibrosis, which increases in severity as the mice age, and eventually the development of HCCs [7]
The major finding of this study is that PDGF-C-induced hepatic fibrosis is dependent on TGF␤ signaling that is regulated by Smad3

Summary

Introduction

CHRONIC LIVER INJURY results in liver fibrosis, which may progress to cirrhosis [31, 42, 45], increasing the risk of developing hepatocellular carcinoma (HCC) [52]. Stimulation of PDGF receptors induces HSC proliferation in vitro [44, 61], and overexpression of PDGF-A, -B, or -C in the liver [7, 9, 53] results in fibrosis. Hepatic overexpression of PDGF-C results in progressive liver disease, development of tumors, and decreased life span [7], phenotypes not seen when PDGF-A or -B is overexpressed in the liver [9, 53]. We have previously reported that hepatic overexpression of PDGF-C results in progressive liver fibrosis, which increases in severity as the mice age, and eventually the development of HCCs [7]. Correlation between collagen deposition, HSC activation, and elevated levels of Tgf␤1 suggests that TGF␤ may be a critical regulator in this mouse model of fibrosis. It is plausible that differences in the amount of TGF␤ produced in each of these models [7, 9, 53] may account for the observed differences in the severity of chronic liver disease in these models

Methods

Results

Conclusion