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 ALK5/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.

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

“…6, a and b). Also TGF-␤1 may activate noncanonical p38 MAPK and the JNK/SAPK family (43). Here, phosphorylation of p38 and SAPK/JNK remained unchanged (Fig.…”

An engineered transforming growth factor β (TGF-β) monomer that functions as a dominant negative to block TGF-β signaling

“…The TGF-␤s are responsible for promoting the progression of numerous human diseases (11)(12)(13)44), yet despite nearly 2 decades of preclinical studies and clinical trials, no inhibitors have been approved for use in humans. The results presented here demonstrate that an engineered TGF-␤ monomer, lacking Cys-77 and the heel ␣-helix (␣3), functions to potently block and inhibit signaling of the TGF-␤1, -␤2, and -␤3 with IC 50 values in the range of 20 -70 nM ( Fig.…”

“…These include connec-tive tissue disorders, such as Marfan's disease and Loeys-Dietz syndrome, which are caused by increased or decreased signaling due to mutations in the matrix protein fibrillin-1 or T␤RII, respectively (10,11). The dysregulation of the pathway is also responsible for fibrotic disorders (12) and soft tissue cancers (13). The fibrotic disorders are a result of hyperactive TGF-␤ signaling following tissue injury or disease progression that leads to the accumulation of extracellular matrix proteins.…”

Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist

“…4). TGF-β1 and CTGF play a key role in the progression and pathogenesis of liver fibrosis (2,11,23). At 12 weeks after the initiation of CCl 4 injection, the hepatic gene expressions of TGF-β1 and CTGF were increased 3.8-and 3.1-fold in mice, respectively, compared with saline-injected normal mice.…”

“…Growth factors play roles in the cellular and molecular pathways that lead to fibrogenic events. Among the growth factors, transforming growth factor-β1 (TGF-β1) is a key mediator of fibrogenesis (2,11,23). TGF-β1 transcriptionally activates the expression of connective tissue growth factor (CTGF) ONO-1301.…”