Zinc-Alpha-2-Glycoprotein Peptide Downregulates Type I and III Collagen Expression via Suppression of TGF-β and p-Smad 2/3 Pathway in Keloid Fibroblasts and Rat Incisional Model

Abstract

Background:Keloids and hypertrophic scars result from abnormal collagen accumulation and the inhibition of its degradation. Although the pathogenesis remains unclear, excessive accumulation of the extracellular matrix (ECM) is believed to be associated with the TGF-beta/SMAD pathway. Zinc-alpha-2-glycoprotein (ZAG) inhibits TGF-beta-mediated epithelial-to-mesenchymal transdifferentiation and impacts skin barrier functions. In this study, we investigated the potential of a small ZAG-derived peptide against hypertrophic scars and keloids.Methods:The study examined cell proliferation and mRNA expression of collagen types I and III in human dermal fibroblast (HDF) cell lines and keloid-derived fibroblasts (KF) following ZAG peptide treatment. A rat incisional wound model was used to evaluate the effect of ZAG peptide in scar tissue.Results:Significantly lower mRNA levels of collagen types I and III were observed in ZAG-treated fibroblasts, whereas matrix metalloproteinase (MMP)-1 and MMP-3 mRNA levels were significantly increased in HDFs and KFs. Furthermore, ZAG peptide significantly reduced protein expression of collagen type I and III, TGF-beta 1, and p-Smad2/3 complex in KFs. Rat incisional scar models treated with ZAG peptide presented narrower scar areas and reduced immature collagen deposition, along with decreased expression of collagen type I, alpha-SMA, and p-Smad2/3.Conclusion:ZAG peptide effectively suppresses the TGF-beta and p-Smad2/3 pathway and inhibits excessive cell proliferation during scar formation, suggesting its potential therapeutic implications against keloids and hypertrophic scars.