TGF-β signaling in fibrosis

Transforming growth factor beta (TGF-beta) is a central mediator of fibrogenesis. TGF-beta 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-beta 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-beta has emerged as an attractive therapeutic target. However, the pleiotropic and multifunctional effects of TGF-beta and its role in tissue homeostasis, immunity and cell proliferation raise concerns regarding potential side effects that may be caused by TGF-beta blockade. This minireview summarizes the role of TGF-beta signaling pathways in the fibrotic response.