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 unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We 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 cells.In 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 mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More 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 signaling.Our 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.
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。
