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)-b signaling as a fibronectin-independent mechanism of type I collagen fibrillogenesis following adult liver injury. To address the contribution of TGF-b signaling during the development of liver fibrosis, we generated adult mice lacking TGF-b type II receptor (TGF-bIIR) from the liver. TGF-bIIR 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-bIIR knockout livers colocalized well with fibronectin. We provide evidence that elimination of TGF-bIIR is not sufficient to completely prevent liver fibrosis. Our results indicate a TGF-beindependent mechanism of type I collagen production and suggest connective tissue growth factor as its potent mediator. We advocate combined elimination of TGF-b signaling and connective tissue growth factor as a potential therapeutic target by which to attenuate liver fibrosis. (Am J Pathol 2014 http://dx

Expression and clinical significance of connective tissue growth factor (CTGF) in Graves' ophthalmopathy

“…Evidence has been introduced and suggested that overexpression of CTGF has been noted in numerous fibrotic disorders, including pulmonary,12 renal,13 hepatic,14 skin15 and cardiac fibrosis 11 16. In our previous study, we first demonstrated a significant upregulation of mRNA and protein expression levels of CTGF in the GO orbital fibroblasts as compared with those of normal controls 17.…”

SIRT1 antagonizes liver fibrosis by blocking hepatic stellate cell activation in mice

“…TGF-b, for instance, is the dominant and prototypical profibrogenic factor in liver fibrosis. Mice with deficiencies in the TGF-b signaling pathway, including TGF-b receptor (9) and SMAD proteins (10,11), display resistance to liver fibrosis. On the other hand, transgenic mice with liver-specific ABBREVIATIONS: AcH3, acetylated H3; ALT, alanine aminotransferase; a-SMA, a smooth muscle actin; AST, aspartate aminotransferase; BDL, bile duct ligation; ChIP, chromatin immunoprecipitation; cKO, conditional knockout; DZNep, 3-deazaneplanocin A; ECM, extracellular matrix; EZH2, enhancer of zeste homolog 2; H3K27Me3, trimethylated histone 3 lysine 27; H3K4Me3, trimethylated histone 3 lysine 4; HSC, hepatic stellate cell; PPARg, peroxisome proliferator activated receptor g; qPCR, quantitative PCR; Rosi, rosiglitazone; siRNA, small interfering RNA; SIRT1, silent information regulator 1; WT, wild type overexpression of TGF-b are more prone to develop fibrosis when exposed to CCl 4 (12) or LPS (13).…”

Mechanisms of Collagen Network Organization in Response to Tissue/Organ Damage

“…These findings indicate that TGF-β signaling is indeed a dominant pathway in the development of liver fibrosis [62]. However, elimination of TGF-β or TRII does not completely prevent the accumulation of Col I in chronic liver injury, and in particular, TRII knockout livers still remain ~46.4% fibrosis compared to wild type [61,62]. Therefore, these findings clearly indicate the TGF-β-independent mechanism(s) in the development of liver fibrosis (see Section 3).…”

“…We hypothesized that the removal of fibronectin or TGF-β signaling in vivo could prevent extensive ECM network formation following tissue damage. To define the functional identity of fibronectin and TGF-β signaling in adult tissue remodeling, we recently established two animal models lacking fibronectin (both isoforms) or TRII, respectively, in adult liver [14,62]. Our new findings suggest fibronectin-/TGF-β-independent mechanisms are involved in the development of liver fibrosis.…”

“…Knockout livers actually show significantly lower ECM deposition (~46% compared to controls) in carbon tetrachloride (CCl 4 )-induced chronic injury, which is accompanied by the decreased expression of myofibroblast marker alpha-smooth muscle actin (α-SMA). These findings indicate that TGF-β signaling is indeed a dominant pathway in the development of liver fibrosis [62]. However, elimination of TGF-β or TRII does not completely prevent the accumulation of Col I in chronic liver injury, and in particular, TRII knockout livers still remain ~46.4% fibrosis compared to wild type [61,62].…”