ADAM Metallopeptidase domain 19 promotes skin fibrosis in systemic sclerosis via neuregulin-1

作者：Qiming Meng, Ding Bao, Sijia Liu, Jing Huang, Muyao Guo, Bingying Dai, Liqing Ding, Shasha Xie, Meng Meng, Chunliu Lv, Weijia He, Hui Luo, Honglin Zhu · 发表于：Molecular Medicine · 年份：2024 · DOI：10.1186/s10020-024-01047-8 · 被引用次数：13 · 研究领域：Systemic Sclerosis and Related Diseases、Rheumatoid Arthritis Research and Therapies、Connective Tissue Growth Factor Research

BACKGROUND: ADAM19 (ADAM Metallopeptidase Domain 19) is known to be involved in extracellular matrix (ECM) remodeling, yet its specific function in systemic sclerosis (SSc) fibrosis remains unclear. OBJECTIVES: This study sought to clarify the role and underlying mechanism of ADAM19 in SSc skin fibrosis. METHODS: The expression of ADAM19 was assessed in skin tissues of SSc and wound healing using publicly available transcriptome datasets. This analysis was further validated through real-time PCR, western blot, and immunostaining in our SSc cohort, as well as in a mouse model of hypochlorite (HOCl)-induced fibrosis. To downregulate the expression of ADAM19, ADAM19 siRNA was employed. The influence of ADAM19 on fibroblast transcriptomics was examined using bulk RNA-seq. Data analysis and visualization were conducted using R packages, including edgeR, limma, clusterProfiler, ggplot2, gseaplot2, and complexheatmap. RESULTS: ADAM19 exhibited a significant upregulation in skin tissues of SSc patients, as well as in wound healing and a HOCl-induced fibrosis mouse model. Additionally, there was a notable positive correlation between ADAM19 and fibrosis-related genes, local skin score, Modified Rodnan skin score, skin thickness progression rate, and the presence of ARA antibodies in SSc patients. Furthermore, ADAM19 levels were markedly elevated in SSc primary dermal fibroblasts and TGF-β-stimulated healthy controls primary dermal fibroblasts. The downregulation of ADAM19 resulted in ...