TGF-β signaling in fibrosis

Abstract

Transforming growth factor β (TGF-β) is a central mediator of fibrogenesis. TGF-β is upregulated and activated in fibrotic diseases and modulates fibroblast phenotype and function, inducing myofibroblast transdifferentiation while promoting matrix preservation. Studies in a wide range of experimental models have demonstrated the involvement of the canonical activin receptor-like kinase 5/Smad3 pathway in fibrosis. Smad-independent pathways may regulate Smad activation and, under certain conditions, may directly transduce fibrogenic signals. The profibrotic actions of TGF-β are mediated, at least in part, through induction of its downstream effector, connective tissue growth factor. In light of its essential role in the pathogenesis of fibrosis, TGF-β has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-β and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-β blockade. This minireview summarizes the role of TGF-β signaling pathways in the fibrotic response.

Figure 1

Activation of TGF-β requires liberation of the TGF-β dimer from an inactive latent complex with the LAP (see text). TGF-β signals through Smad-dependent and Smad-independent pathways. Activation of the canonical ALK5/Smad3 pathway plays a central role in the pathogenesis of fibrosis. Smad-independent pathways may regulate Smad signaling or exert direct fibrogenic actions.

Figure 2

Effects of TGF-β on fibroblast phenotype and function.