New insights into TGF-β/Smad signaling in tissue fibrosis

Abstract

Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

Novel role of the clustered miR‐23b‐3p and miR‐27b‐3p in enhanced expression of fibrosis‐associated genes by targeting TGFBR3 in atrial fibroblasts

“…38,39 Our present study has confirmed that the Smad3 signalling pathway was activated in Ang-II-treated HAFs. 38,39 Our present study has confirmed that the Smad3 signalling pathway was activated in Ang-II-treated HAFs.…”

Tamoxifen affects chronic pancreatitis‐related fibrogenesis in an experimental mouse model: an effect beyond Cre recombination

“…Our observation of opposite directions of Tgfb1 mRNA and Col1a1 mRNA expression in male PSCs after tamoxifen treatment has been observed in fibroblasts in other studies as well . One possible explanation might be that tamoxifen enhances the TGF‐β‐induced expression of the inhibitory Smad7 to exert suppression of certain TGF‐β response genes , or higher levels of matrix metalloproteinase are generated, tipping the balance toward ECM degradation . In our experiments, the increased Col1a1 mRNA in tamoxifen‐treated female PSCs seemed not related to the Tgfb1 mRNA levels, suggesting that other mechanisms were involved in this scenario.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Small molecules have a long history of acting as drugs for the treatment of hypertension, infections, heart failure, diabetes, asthma, rhinitis, and tumors and comprise approximately 75% of the anticancer drugs approved by the FDA from 1981 to 2014 . Recently, many small molecules target EMT and exhibit good therapeutic effects on retarding progressive tissue fibrosis and cancer in experimental conditions . In addition, it is worth noting that many small molecules, such as tivantinib, trametinib, linsitinib, nintedanib, and binimetinib, are in ongoing clinical trials for the treatment of tumors .…”

“…11 Recently, many small molecules target EMT and exhibit good therapeutic effects on retarding progressive tissue fibrosis and cancer in experimental conditions. [12][13][14] In addition, it is worth noting that many small molecules, such as tivantinib, trametinib, linsitinib, nintedanib, and binimetinib, are in ongoing clinical trials for the treatment of tumors. 2 These cases show promising prospects for treating fibrosis and cancer, which encourages researchers to find effective small molecule drugs for treating fibrosis and cancer.In this review, we describe some important transcription factors, signaling pathways, RNA-binding proteins and microRNAs (miRNAs) and several novel regulators that contribute to EMT and further present some small FENG ET AL.…”