Profibrotic role of the SOX9-MMP10-ECM biosynthesis axis in the tracheal fibrosis after injury and repair  

作　　者：Lei Gu Anmao Li Chunyan He Rui Xiao Jiaxin Liao Li Xu Junhao Mu Xiaohui Wang Mingjin Yang Jinyue Jiang Yang Bai Xingxing Jin Meiling Xiao Xia Zhang Tairong Tan Yang Xiao Jing Lin Yishi Li Shuliang Guo 

机构地区：[1]Department of Respiratory and Critical Care Medicine,The First Affiliated Hospital of Soochow University,Suzhou 215006,China [2]Department of Respiratory and Critical Care Medicine,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [3]Department of Infection Disease,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang 325000,China

出　　处：《Genes & Diseases》2024年第5期360-373,共14页基因与疾病（英文）

基　　金：the National Natural Science Foundation of China(No.82370098);National Major Science and Technology Projects of China(No.2018ZX10302302003);Chongqing Talents projects-Famous Masters and Teachers(Shuliang Guo);Chongqing Young and Middle-aged Medical High-end Talent Studio e Lung Nodule Studio,and the Postgraduate Research and Innovation Project of Chongqing,China(No.CYB21173).

摘　　要：Fibroblast activation and extracellular matrix(ECM)deposition play an important role in the tracheal abnormal repair process and fibrosis.As a transcription factor,SOX9 is involved in fibroblast activation and ECM deposition.However,the mechanism of how SOX9 regulates fibrosis after tracheal injury remains unclear.We investigated the role of SOX9 in TGF-b1-induced fibroblast activation and ECM deposition in rat tracheal fibroblast(RTF)cells.SOX9 overexpression adenovirus(Ad-SOX9)and siRNA were transfected into RTF cells.We found that SOX9 expression was up-regulated in RTF cells treated with TGF-b1.SOX9 overexpression activated fibroblasts and promoted ECM deposition.Silencing SOX9 inhibited cell proliferation,migration,and ECM deposition,induced G2 arrest,and increased apoptosis in RTF cells.RNA-seq and chromatin immunoprecipitation sequencing(ChIP-seq)assays identified MMP10,a matrix metalloproteinase involved in ECM deposition,as a direct target of SOX9,which promotes ECM degradation by increasing MMP10 expression through the Wnt/b-catenin signaling pathway.Furthermore,in vivo,SOX9 knockdown ameliorated granulation proliferation and tracheal fibrosis,as manifested by reduced tracheal stenosis.In conclusion,our findings indicate that SOX9 can drive fibroblast activation,cell proliferation,and apoptosis resistance in tracheal fibrosis via the Wnt/b-catenin signaling pathway.The SOX9eMMP10 eECM biosynthesis axis plays an important role in tracheal injury and repair.Targeting SOX9 and its downstream target MMP10 may represent a promising therapeutic approach for tracheal fibrosis.

关 键 词：Extracellular matrix deposition Fibroblast activation MMP10 SOX9 Tracheal fibrosis 

分 类 号：R563[医药卫生—呼吸系统]