title: Transforming growth factor-β-independent role of connective tissue growth factor in the development of liver fibrosis.
abstract: We previously identified transforming growth factor (TGF)-β signaling as a fibronectin-independent mechanism of type I collagen fibrillogenesis following adult liver injury. To address the contribution of TGF-β signaling during the development of liver fibrosis, we generated adult mice lacking TGF-β type II receptor (TGF-βIIR) from the liver. TGF-βIIR knockout livers indeed showed a dominant effect in reducing fibrosis, but fibrosis still remained approximately 45% compared with control and fibronectin knockout livers. Unexpectedly, this was accompanied by significant up-regulation of connective tissue growth factor mRNA levels. Organized type I collagen networks in TGF-βIIR knockout livers colocalized well with fibronectin. We provide evidence that elimination of TGF-βIIR is not sufficient to completely prevent liver fibrosis. Our results indicate a TGF-β-independent mechanism of type I collagen production and suggest connective tissue growth factor as its potent mediator. We advocate combined elimination of TGF-β signaling and connective tissue growth factor as a potential therapeutic target by which to attenuate liver fibrosis.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Safdar
authors.initials: S
authors.lastname: Jawaid
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Musculoskeletal Biology, Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: sakait@liverpool.ac.uk.
authors.forename: Takao
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002908:Chronic Disease; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; D005353:Fibronectins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D002251:Carbon Tetrachloride; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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