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

摘要

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-@b-independent 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.