Wnt4 Negatively Regulates The Tgf-Beta 1-Induced Human Dermal Fibroblast-To-Myofibroblast Transition Via Targeting Smad3 And Erk

Abnormal activation of Wnt signaling has been demonstrated in the wound healing process and the pathogenesis of fibrotic disorders, with Wnt4 specifically identified as having a key role in the pathogenesis of renal, pulmonary and liver fibrosis. Wnt4 also was found to be upregulated by transforming growth factor-beta 1 (TGF-beta 1) in fetal and postnatal murine fibroblasts and bone marrow mesenchymal cells, suggesting an underlying cooperation between Wnt4 and TGF-beta 1 in fibrosis. However, the specific roles of Wnt4 in TGF-beta 1-induced skin myofibroblast transition and hypertrophic scar formation remain unclear. In the present study, we first observed reduced Wnt4 expression in hypertrophic scar tissue compared with that in normal skin tissue. Following upregulation by TGF-beta 1, Wnt4 inhibited the TGF-beta 1-induced transdifferentiation of fibroblasts into myofibroblasts. Using fibroblast-populated collagen lattice contraction assays, we showed that the increased contractility induced by TGF-beta 1 was significantly blocked by exogenous Wnt4 and the alpha-smooth muscle actin (alpha-SMA) expression was decreased in fibroblasts in the collagen lattices. In addition, knockdown of Wnt4 resulted in further increases in alpha-SMA and collagen I expressions. Further investigation showed that Wnt4 could inhibit the autocrine effect of TGF-beta 1 as well as block the phosphorylation of Smad3 and ERK but not of AKT or JNK. Lastly, using hypertrophic scar-derived fibroblasts, we showed that the elevated alpha-SMA and collagen I levels were markedly reduced after treatment with Wnt4. Taken together, our results suggest that Wnt4 negatively regulates TGF-beta 1-induced fibroblast activation, which may represent a novel therapeutic strategy for the treatment and prevention of hypertrophic scars.