Notch1 signaling regulates Sox9 and VEGFA expression and governs BMP2-induced endochondral ossification of mesenchymal stem cells  

作　　者：Jing Zou Chengcheng Du Senrui Liu Piao Zhao Shengqiang Gao Bowen Chen Xiangdong Wu Wei Huang Zhenglin Zhu Junyi Liao 

机构地区：[1]Department of Orthopaedic Surgery,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [2]Chongqing Health Commission Key Laboratory of Motor System Regenerative and Translational Medicine,Orthopaedic Research Laboratory of Chongqing Medical University,Chongqing 400016,China [3]Molecular Oncology Laboratory,Department of Orthopaedic Surgery and Rehabilitation Medicine,The University of Chicago Medical Center,Chicago,IL 60637,USA [4]Department of Orthopaedic Surgery,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100730,China

出　　处：《Genes & Diseases》2025年第3期567-583,共17页基因与疾病(英文)

基　　金：supported by the Science and Technology Research Program of the Chongqing Education Commission(China)(No.KJQN202100431,KJZDM202100401);supported by the National Natural Science Foundation of China(No.81972069,82002312);CQMU Program for Youth Innovation in Future Medicine(Chongqing,China)(No.W0154);Innovation Project from Chongqing Municipal Education Commission(China)(No.CYB21169);Cultivating Program and Candidate of TipTop Talent of The First Affiliated Hospital of Chongqing Medical University(Chongqing,China)(No.BJRC2021-04);Cultivating Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University(Chongqing,China)(No.CYYY-BSHPYXM-202202);Special Support from Chongqing Postdoctoral Research Program(Chongqing,China)(No.2021XM1029);upported by a postdoctoral fellowship from Chongqing Medical University and rewarded by China Postdoctoral Science Foundation(No.2022M720605).

摘　　要：Although bone morphogenetic protein 2 (BMP2) can induce chondrogenic differentiation of mesenchymal stem cells (MSCs), its induction of endochondral ossification limits theapplication of BMP2-based cartilage regeneration. Here, we clarified the mechanisms of BMP2-induced endochondral ossification of MSCs. In vitro and in vivo chondrogenic, osteogenic, andangiogenic differentiation models of MSCs were constructed. The expression of target geneswas identified at both protein and mRNA levels. RNA sequencing, molecular docking, co-immunoprecipitation, and chromatin immunoprecipitation followed by sequencing were applied toinvestigate the molecular mechanisms. We found that BMP2 up-regulated the expression ofNotch receptors and ligands in MSCs. Notch1 signaling activation was related to inhibition of chondrogenic differentiation, promotion of osteogenic and angiogenic differentiation. In vivoectopic stem cell implantation identified that Notch1 signaling activation blocked BMP2-induced chondrogenesis and facilitated endochondral ossification of MSCs. Mechanistically,we elucidated Notch1 intracellular domain (NICD1)-RBPjk complex binding to SRY-box transcription factor 9 (Sox9) and vascular endothelial growth factor A (VEGFA) promoters todecrease Sox9 expression and increase VEGFA expression. These findings suggest that Notch1signaling can regulate BMP2-induced endochondral ossification by promoting RBPjk-mediatedSox9 inactivation and VEGFA expression. It is conceivable that targeting Notch1 signaling mediated endochondral ossification would benefit BMP2-based cartilage regeneration.

关 键 词：BMP2 Chondrogenic differentiation Endochondral ossification Mesenchymal stem cells Notch1 signaling 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]