Human xylosyltransferase-I - a new marker for myofibroblast differentiation in skin fibrosis

Abstract

Skin fibrosis is a severe type of fibrotic disorder emerging in terms of hypertrophic scars or systemic sclerosis. Key event of fibrogenesis is the transition of fibroblasts to matrix-producing myofibroblasts. In the presence of fibrotic triggers, for instance secretion of profibrotic growth factors like transforming growth factor-β1 (TGF-β1) or mechanical strain, myofibroblasts persist. Current research focuses on discovering innovative myofibroblast biomarkers which are regulated in fibrotic development and accessible for antifibrotic inhibition. Here, we consider the suitability of xylosyltransferase-I (XT-I) as a myofibroblast biomarker in skin fibrosis. XT-I catalyzes the initial step of glycosaminoglycan biosynthesis. Its increase in enzymatic activity is known to refer only to manifested diseases which are characterized by an abnormal rate of proteoglycan biosynthesis. In this study, treatment of normal human dermal fibroblasts (NHDF) with TGF-β1 was followed by increased relative XYLT1 mRNA expression. Remarkably, this upregulation was strongly dependent on myofibroblast content, increasing during fibrogenesis. Moreover, XT activity increased time-dependently in response to progressive myofibroblast transformation. XYLT1 expression was inhibited by TGF-β receptor I (ALK5) inhibitor SB431542. In contrast, XYLT2 expression was only marginally affected by TGF-β1 as well as ALK5 inhibition. Our results strengthen the significance of XT expression and activity in fibrotic remodeling. Therefore, we propose XT activity, in addition to α-SMA expression, as a new biomarker for myofibroblast differentiation and fibrotic development. Further studies are now needed to evaluate the option to control and inhibit fibrotic remodeling by interfering with XT expression.

Keywords: ALK5; Biomarker; Dermal fibroblast; Dpm; Fibrogenesis; GAG; Myofibroblast; NHDF; RT-PCR; Skin fibrosis; TGF-β1; XT/XYLT; Xylosyltransferase; alpha-smooth muscle actin; disintegrations per minute; glycosaminoglycan; normal human dermal fibroblast; quantitative real-time pcr; transforming growth factor-β receptor I; transforming growth factor-β1; xylosyltransferase; α-SMA/ACTA2.