CD109 Deletion Promotes Myofibroblast Differentiation and Smad-Dependent Matrix Accumulation in Skin Fibrosis.

Abstract

Skin fibrosis is characterized by excessive extracellular matrix (ECM) deposition, leading to tissue dysfunction and scarring. Transforming growth factor (TGF)-β is a central mediator of fibrosis. We previously identified CD109 as a TGF-β co-receptor and negative regulator of TGF-β signaling and fibrotic responses and showed that its epidermal overexpression reduces dermal fibrosis in vivo. However, the effects of CD109 loss in the dermis remain unclear. The current study investigates the impact of CD109 knockout (KO) on skin fibrosis using a bleomycin-induced fibrosis mouse model. Following bleomycin treatment, CD109 KO mice showed increased collagen I deposition and elevated fibronectin, CCN2, and α-smooth muscle actin expression in the skin, indicating enhanced ECM production and myofibroblast differentiation compared with wild-type mice. Additionally, CD109 KO mice displayed enhanced Smad1 and Smad2/3 phosphorylation in the skin, indicating heightened TGF-β signaling. In vitro, CD109 KO fibroblasts exhibited increased TGF-β-induced migration and collagen contraction. These findings suggest that CD109 deficiency exacerbates dermal fibrosis by promoting TGF-β/Smad signaling and myofibroblast activation. Given its dysregulation in fibrotic disorders such as scleroderma, our results identify CD109 as a key regulator of skin homeostasis by modulating ECM production and fibroblast activation, underscoring its potential as a therapeutic target in fibrotic disorders.