| First Author | Lee JI | Year | 2016 |
| Journal | Am J Physiol Cell Physiol | Volume | 310 |
| Issue | 6 | Pages | C436-45 |
| PubMed ID | 26632601 | Mgi Jnum | J:232654 |
| Mgi Id | MGI:5779762 | Doi | 10.1152/ajpcell.00423.2014 |
| Citation | Lee JI, et al. (2016) Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis. Am J Physiol Cell Physiol 310(6):C436-45 |
| abstractText | 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-beta (TGFbeta) 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 TGFbeta 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 TGFbeta/Smad3 signaling pathways to regulate HSC proliferation, collagen production and ultimately fibrosis. In summary, these results suggest that inhibition of both PDGF and TGFbeta signaling pathways may be required to effectively attenuate fibrogenesis in patients with chronic liver disease. |
