A critical role of AREG for bleomycin-induced skin fibrosis

Cell & Bioscience

Shuyi Fang¹  Jun Wan²  Yunlong Liu²  Xiaoli Zhang³  Dongsheng Gu³  Mary Yinghua Zhang³  Jingwu Xie⁴  Hongyu Gao⁵ 

[1] Department of BioHealth Informatics, School of Informatics and Computing At IUPUI, Indiana University, Indianapolis, IN, USA;Department of BioHealth Informatics, School of Informatics and Computing At IUPUI, Indiana University, Indianapolis, IN, USA;The IU Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA;The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Pediatrics, The Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA;Department of Pediatrics, The Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA;The IU Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA;The IU Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA;

关键词: Scleroderma;    Skin fibrosis;    Bleomycin;    Areg;    MEK;   

DOI  :  10.1186/s13578-021-00553-0

来源: Springer

【 摘 要 】

We report our discovery of an important player in the development of skin fibrosis, a hallmark of scleroderma. Scleroderma is a fibrotic disease, affecting 70,000 to 150,000 Americans. Fibrosis is a pathological wound healing process that produces an excessive extracellular matrix to interfere with normal organ function. Fibrosis contributes to nearly half of human mortality. Scleroderma has heterogeneous phenotypes, unpredictable outcomes, no validated biomarkers, and no effective treatment. Thus, strategies to slow down scleroderma progression represent an urgent medical need. While a pathological wound healing process like fibrosis leaves scars and weakens organ function, oral mucosa wound healing is a scarless process. After re-analyses of gene expression datasets from oral mucosa wound healing and skin fibrosis, we discovered that several pathways constitutively activated in skin fibrosis are transiently induced during oral mucosa wound healing process, particularly the amphiregulin (Areg) gene. Areg expression is upregulated ~ 10 folds 24hrs after oral mucosa wound but reduced to the basal level 3 days later. During bleomycin-induced skin fibrosis, a commonly used mouse model for skin fibrosis, Areg is up-regulated throughout the fibrogenesis and is associated with elevated cell proliferation in the dermis. To demonstrate the role of Areg for skin fibrosis, we used mice with Areg knockout, and found that Areg deficiency essentially prevents bleomycin-induced skin fibrosis. We further determined that bleomycin-induced cell proliferation in the dermis was not observed in the Areg null mice. Furthermore, we found that inhibiting MEK, a downstream signaling effector of Areg, by selumetinib also effectively blocked bleomycin-based skin fibrosis model. Based on these results, we concluded that the Areg-EGFR-MEK signaling axis is critical for skin fibrosis development. Blocking this signaling axis may be effective in treating scleroderma.

【 授权许可】

CC BY