title: Molecular Mechanism Responsible for Fibronectin-controlled Alterations in Matrix Stiffness in Advanced Chronic Liver Fibrogenesis.
abstract: Fibrosis is characterized by extracellular matrix (ECM) remodeling and stiffening. However, the functional contribution of tissue stiffening to noncancer pathogenesis remains largely unknown. Fibronectin (Fn) is an ECM glycoprotein substantially expressed during tissue repair. Here we show in advanced chronic liver fibrogenesis using a mouse model lacking Fn that, unexpectedly, Fn-null livers lead to more extensive liver cirrhosis, which is accompanied by increased liver matrix stiffness and deteriorated hepatic functions. Furthermore, Fn-null livers exhibit more myofibroblast phenotypes and accumulate highly disorganized/diffuse collagenous ECM networks composed of thinner and significantly increased number of collagen fibrils during advanced chronic liver damage. Mechanistically, mutant livers show elevated local TGF-β activity and lysyl oxidase expressions. A significant amount of active lysyl oxidase is released in Fn-null hepatic stellate cells in response to TGF-β1 through canonical and noncanonical Smad such as PI3 kinase-mediated pathways. TGF-β1-induced collagen fibril stiffness in Fn-null hepatic stellate cells is significantly higher compared with wild-type cells. Inhibition of lysyl oxidase significantly reduces collagen fibril stiffness, and treatment of Fn recovers collagen fibril stiffness to wild-type levels. Thus, our findings indicate an indispensable role for Fn in chronic liver fibrosis/cirrhosis in negatively regulating TGF-β bioavailability, which in turn modulates ECM remodeling and stiffening and consequently preserves adult organ functions. Furthermore, this regulatory mechanism by Fn could be translated for a potential therapeutic target in a broader variety of chronic fibrotic diseases.
authors.affiliation: From the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom, the Graduate School of Biomedical Engineering and.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: From the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom, the Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: the Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.affiliation: the Department of Biochemistry, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: the Micro-Imaging Center, Shriners Hospital for Children, Portland, Oregon 97231.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Centre for Materials and Structures, School of Engineering, University of Liverpool, Liverpool L69 3GH, United Kingdom.
authors.forename: Riaz
authors.initials: R
authors.lastname: Akhtar
authors.affiliation: Department of Gastroenterology and Hepatology, and Transfusion Medicine and Cell Therapy, Toyama University, Toyama 930-0194, Japan, and.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Miyazono
authors.affiliation: Department of Gastroenterology and Hepatology, and Transfusion Medicine and Cell Therapy, Toyama University, Toyama 930-0194, Japan, and.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasumura
authors.affiliation: the Graduate School of Biomedical Engineering and.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Environmental and Information Science, Yokohama National University, Yokohama 240-8501, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Morishita
authors.affiliation: From the MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, United Kingdom, the Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, sakait@liverpool.ac.uk.
authors.forename: Takao
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000818:Animals; D001682:Biological Availability; D002251:Carbon Tetrachloride; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000172:deficiency / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005353:Fibronectins; D016212:Transforming Growth Factor beta; D003094:Collagen; D002251:Carbon Tetrachloride; D008249:Protein-Lysine 6-Oxidase
keywords: chronic hepatic fibrogenesis; conditional knockout mouse; extracellular matrix; fibronectin; liver injury; lysyl oxidase; tissue stiffness; transforming growth factor beta (TGF-B)