Transforming growth factor-β-independent role of connective tissue growth factor in the development of liver fibrosis

Keiko Sakai; Safdar Jawaid; Takako Sasaki; George Bou-Gharios; Takao Sakai

doi:10.1016/j.ajpath.2014.06.009

Transforming growth factor-β-independent role of connective tissue growth factor in the development of liver fibrosis

Am J Pathol. 2014 Oct;184(10):2611-7. doi: 10.1016/j.ajpath.2014.06.009. Epub 2014 Aug 7.

Authors

Keiko Sakai¹, Safdar Jawaid², Takako Sasaki³, George Bou-Gharios⁴, Takao Sakai⁵

Affiliations

¹ 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.
² Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
³ Department of Biochemistry, Faculty of Medicine, Oita University, Oita, Japan.
⁴ Department of Musculoskeletal Biology, Institute of Aging and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
⁵ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbon Tetrachloride / toxicity
Chronic Disease
Collagen Type I / genetics
Collagen Type I / metabolism
Connective Tissue Growth Factor / genetics
Connective Tissue Growth Factor / metabolism*
Disease Models, Animal
Fibronectins / genetics
Fibronectins / metabolism
Gene Expression Regulation*
Humans
Liver / drug effects
Liver / metabolism
Liver / pathology
Liver Cirrhosis / chemically induced
Liver Cirrhosis / metabolism*
Liver Cirrhosis / pathology
Mice
Mice, Knockout
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
RNA, Messenger / genetics
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta / genetics
Receptors, Transforming Growth Factor beta / metabolism*
Signal Transduction*
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism*
Up-Regulation

Substances

CCN2 protein, mouse
Collagen Type I
Fibronectins
RNA, Messenger
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
Connective Tissue Growth Factor
Carbon Tetrachloride
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type II

Abstract

Publication types

MeSH terms

Substances

Grants and funding