Shuhong Guan1, Jun Zhou2. 1. Department of Respiratory, The First People's Hospital of Changzhou, Changzhou 213003, Jiangsu, China. 2. Department of Respiratory, The First People's Hospital of Changzhou, Changzhou 213003, Jiangsu, China. Electronic address: zhouyfan000@163.com.
Abstract
Pulmonary fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix. Both TGF-β and Wnt signaling have been implicated in the regulation of organ fibrosis. However little is known about whether TGF-β-induced gene expression changes in Wnt signaling pathway could predict disease progression. In the study, we investigated the interaction between TGF-β and Wnt signaling in mediating pulmonary fibrosis by big data analysis, in vitro and in vivo experimental studies and clinical data analysis. We found that TGF-β1 treatment induces a marked upregulation of Frizzled-7 (FZD7) in human lung fibroblasts. FZD7 expression is also increased in animal models of TGF-β1-induced pulmonary fibrosis. TGF-β1 upregulated FZD7 expression in a Smad3-dependent manner. Functionally, knockdown of FZD7 inhibits TGF-β1-induced expression of α-smooth muscle actin (α-SMA), collagen I (Col I), fibronectin and connective tissue growth factor (CTGF). FZD7 inhibition further attenuates TGF-β1-induced pulmonary fibrosis in vivo. Finally our data demonstrated that FZD7 transmits non-canonical Wnt signaling by interacting Wnt5A in the regulation of ECM expression. CONCLUSION: These results suggest that FZD7-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.
Pulmonary fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix. Both TGF-β and Wnt signaling have been implicated in the regulation of organ fibrosis. However little is known about whether TGF-β-induced gene expression changes in Wnt signaling pathway could predict disease progression. In the study, we investigated the interaction between TGF-β and Wnt signaling in mediating pulmonary fibrosis by big data analysis, in vitro and in vivo experimental studies and clinical data analysis. We found that TGF-β1 treatment induces a marked upregulation of Frizzled-7 (FZD7) in human lung fibroblasts. FZD7 expression is also increased in animal models of TGF-β1-induced pulmonary fibrosis. TGF-β1 upregulated FZD7 expression in a Smad3-dependent manner. Functionally, knockdown of FZD7 inhibits TGF-β1-induced expression of α-smooth muscle actin (α-SMA), collagen I (Col I), fibronectin and connective tissue growth factor (CTGF). FZD7 inhibition further attenuates TGF-β1-induced pulmonary fibrosis in vivo. Finally our data demonstrated that FZD7 transmits non-canonical Wnt signaling by interacting Wnt5A in the regulation of ECM expression. CONCLUSION: These results suggest that FZD7-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases.
Authors: Jörg H W Distler; Andrea-Hermina Györfi; Meera Ramanujam; Michael L Whitfield; Melanie Königshoff; Robert Lafyatis Journal: Nat Rev Rheumatol Date: 2019-11-11 Impact factor: 20.543