Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/β-catenin signaling

作     者：Ri-Xu Liu Rong-He Gu Zhi-Peng Li Zhi-Quan Hao Qin-Xiao Hu Zhen-Yan Li Xiao-Gang Wang Wang Tang Xiao-He Wang Yu-Kai Zeng Zhen-Wei Li Qiu Dong Xiao-Feng Zhu Di Chen Ke-Wei Zhao Rong-Hua Zhang Zhen-Gang Zha Huan-Tian Zhang Ri-Xu Liu;Rong-He Gu;Zhi-Peng Li;Zhi-Quan Hao;Qin-Xiao Hu;Zhen-Yan Li;Xiao-Gang Wang;Wang Tang;Xiao-He Wang;Yu-Kai Zeng;Zhen-Wei Li;Qiu Dong;Xiao-Feng Zhu;Di Chen;Ke-Wei Zhao;Rong-Hua Zhang;Zhen-Gang Zha;Huan-Tian Zhang

作者机构：Department of Bone and Joint Surgerythe First Affiliated Hospital of Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of EducationJinan UniversityGuangzhou 510630 GuangdongChina Department of Orthopedic and Spine SurgeryThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120 GuangdongChina School of Basic Medical Sciences of Guangxi Medical Universitythe Fifth Affiliated Hospital of Guangxi Medical UniversityNanning 530022 GuangxiChina Key Laboratory of Big Data-Based Precision MedicineSchool of Engineering MedicineBeihang University100191 BeijingChina Guangdong Provincial Key Laboratory of Traditional Chinese Medicine InformatizationCollege of PharmacyJinan UniversityGuangzhou 510630 GuangdongChina Research Center for Computer-aided Drug DiscoveryShenzhen Institute of Advanced TechnologyChinese Academy of Sciences518005 ShenzhenChina Guangzhou Key Laboratory of Chinese Medicine Research on Prevention and Treatment of Osteoporosisthe Third Affiliated Hospital of Guangzhou University of Chinese Medicine510375 GuangzhouChina 

出 版 物：《Bone Research》 (骨研究（英文版）)

年 卷 期：2023年第11卷第4期

页      面：819-833页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by the Natural Science Foundation with grants from the National Key R&D Program of China(2018YFC2002500) National Natural Science Foundation of China(81602360,82072470,82350003,92049201) Key Laboratory Construction Project of Guangzhou Science and Technology Bureau(202102100007) supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01221) Natural Science Foundation of Guangdong Province(2021A1515012154,2019A1515011082,2017A030313665,2018A030313544,2020B1515120038) Science and Technology Projects in Guangzhou(201707010493,202102010069) Macao Foundation for Development of Science and Technology(0029/2019/A) Youth Talent Support Project of Guangzhou Association for Science&Technology(X20200301018) pilot project of clinical collaboration from National Administration of Traditional Chinese Medicine and National Health Commission of the People’s Republic of China and Logistics Support Department of the Central Military Commission 

主　　题：YAP1 osteoporosis depletion 

摘      要：Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely *** recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in ***,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains ***,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis ***,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control *** further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 *** addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control ***,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of *** importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 *** current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.