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

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- β IIR) from the liver. TGF- β IIR 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- β IIR knockout livers colocalized well with fibronectin. We provide evidence that elimination of TGF- β IIR 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.