Objective. Transforming growth factor  (TGF) is a profibrotic cytokine, and its aberrant function is implicated in several types of fibrotic pathologies including scleroderma (systemic sclerosis [SSc]). Multiple lines of evidence show that increased TGF signaling contributes to progressive fibrosis in SSc by promoting fibroblast activation, excessive extracellular matrix (ECM) deposition, and dermal thickening. We have previously identified CD109 as a TGF coreceptor and have shown that it antagonizes TGF signaling and TGF-induced ECM expression in vitro in human keratinocytes and fibroblasts. The aim of the present study was to examine the ability of CD109 to prevent skin fibrosis in a mouse model of bleomycin-induced SSc.Methods. Transgenic mice overexpressing CD109 in the epidermis and their wild-type (WT) littermates were injected with bleomycin in phosphate buffered saline (PBS) or with PBS alone every other day for 21 days or 28 days. Dermal thickness and collagen deposition were determined histologically using Masson's trichrome and picrosirius red staining. In addition, collagen and fibronectin content was analyzed using Western blotting, and activation of TGF signaling was examined by determining phospho-Smad2 and phospho-Smad3 levels using Western blotting and immunohistochemistry.Results. Transgenic mice overexpressing CD109 in the epidermis showed resistance to bleomycininduced skin fibrosis, as evidenced by a significant decrease in dermal thickness, collagen crosslinking, collagen and fibronectin content, and phospho-Smad2/3 levels, as compared to their WT littermates.Conclusion. Our findings suggest that CD109 inhibits TGF signaling and fibrotic responses in experimental murine scleroderma. They also suggest that CD109 regulates dermal-epidermal interactions to decrease extracellular matrix synthesis in the dermis. Thus, CD109 is a potential molecular target for therapeutic intervention in scleroderma.Accumulating evidence indicates that the profibrotic cytokine transforming growth factor  (TGF) is a key factor driving the fibrotic process in scleroderma (systemic sclerosis [SSc]). A large number of studies have demonstrated that TGF signaling is dysregulated in scleroderma (1). Cultured SSc fibroblasts display aberrant activation of autocrine TGF signaling and increased TGF receptor levels, leading to elevated extracellular matrix (ECM) synthesis (2). TGF exacerbates fibrosis through deposition and accumulation of ECM not only by promoting the expression of ECM proteins such as type I collagen and fibronectin (3), but also by reducing ECM degradation through decreased synthesis of matrix metalloproteinases and increased expression of protease inhibitors. Despite the lack of success so far with efforts to develop effective anti-TGF therapies to ameliorate fibrosis, strategies to block the production, activation, and intracellular signaling of TGF are increasingly being explored.TGF signaling is transduced by a pair of transmembrane serine/threonine kinases known as TGF receptor ty...
Background: Transforming Growth Factor Beta (TGFBeta) plays an important role in many biological processes including wound healing and inflammation. However, excess levels of TGF-beta have been linked to scarring and fibrotic skin disorders. Our group has identified CD109 as a novel TGF-Beta co-receptor, and have found that overexpression of CD109 in skin cells in vitro inhibits TGF-Beta1 signalling and reduces extracellular matrix (ECM) deposition. We, therefore, examined whether CD109 is able to regulate ECM production and fibrotic responses in the skin in vivo by studying bleomycin-induced skin fibrosis in transgenic mice overexpressing CD109 in the epidermis.
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