title: Role of Smad3 in platelet-derived growth factor-C-induced liver fibrosis.
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.
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea;
authors.forename: Jung Il
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Jocelyn H
authors.initials: JH
authors.lastname: Wright
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Johnson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Renay L
authors.initials: RL
authors.lastname: Bauer
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sorg
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Yuen
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Hayes
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and.
authors.forename: Lananh
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Department of Surgery, University of Washington, Seattle, Washington.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Riehle
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington; and campjs@u.washington.edu.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000502:physiology; D008103:Liver Cirrhosis / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C411423:platelet-derived growth factor C
keywords: PDGF; Smad; TGFβ; hepatic stellate cells; liver fibrosis