Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss  

作　　者：Xudong Xie Peng Cheng Liangcong Hu Wu Zhou Detai Zhang Samuel Knoedler Guodong Liu Yuan Xiong Hang Xue Yiqiang Hu Barbara Kern Doha Obed Adriana CPanayi Lang Chen Chenchen Yan Ze Lin Guandong Dai Bobin Mi Yingze Zhang Guohui Liu 

机构地区：[1]Department of Orthopedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China [2]Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration,Wuhan 430022,China [3]Department of Clinical Laboratory,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei 430022,P.R.China [4]Division of Plastic Surgery,Brigham and Women’s Hospital,Harvard Medical School,Boston,MA 02152,USA [5]Department of Plastic Surgery and Hand Surgery,Klinikum Rechts der Isar,Technical University of Munich,Munich,Germany [6]Medical Center of Trauma and War Injuries,Daping Hospital,Army Medical University,Chonqing 400042,China [7]Department of Plastic Surgery,Campus CharitéMitte|Campus Virchow-Klinikum,Charité-Universitätsmedizin Berlin,corporate member of Freie Universität Berlin,Humboldt-Universität zu Berlin and Berlin Institute of Health,Berlin,Germany [8]Berlin Institute of Health,Charité-Universitätsmedizin Berlin,Berlin,Germany [9]Department of Plastic,Aesthetic,Hand and Reconstructive Surgery,Hannover Medical School,Hannover,Germany [10]Department of Hand,Plastic and Reconstructive Surgery,Microsurgery,Burn Center,BG Trauma Center Ludwigshafen,University of Heidelberg,Ludwig-Guttmann-Strasse 13,67071 Ludwigshafen/Rhine,Germany [11]Pingshan District People’s Hospital of Shenzhen,Pingshan General Hospital of Southern Medical University,Shenzhen,Guangdong 518118,China [12]Department of Orthopaedic Surgery,The Third Hospital of Hebei Medical University,NO.139 Ziqiang Road,Shijiazhuang 050051,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第2期751-765,共15页信号转导与靶向治疗（英文）

基　　金：supported by the National Key Research&Development Program of China(2021YFA1101500);National Science Foundation of China(No.82002313,No.82072444);Department of Science and Technology of Hubei Province(2021CFB425);Wuhan Science and Technology Bureau(2022020801020464)。

摘　　要：The clinical role and underlying mechanisms of valproic acid(VPA)on bone homeostasis remain controversial.Herein,we confirmed that VPA treatment was associated with decreased bone mass and bone mineral density(BMD)in both patients and mice.This effect was attributed to VPA-induced elevation in osteoclast formation and activity.Through RNA-sequencing,we observed a significant rise in precursor miR-6359 expression in VPA-treated osteoclast precursors in vitro,and further,a marked upregulation of mature miR-6359(miR-6359)in vivo was demonstrated using quantitative real-time PCR(qRT-PCR)and miR-6359 fluorescent in situ hybridization(miR-6359-FISH).Specifically,the miR-6359 was predominantly increased in osteoclast precursors and macrophages but not in neutrophils,T lymphocytes,monocytes and bone marrow-derived mesenchymal stem cells(BMSCs)following VPA stimulation,which influenced osteoclast differentiation and bone-resorptive activity.Additionally,VPA-induced miR-6359 enrichment in osteoclast precursors enhanced reactive oxygen species(ROS)production by silencing the SIRT3 protein expression,followed by activation of the MAPK signaling pathway,which enhanced osteoclast formation and activity,thereby accelerating bone loss.Currently,there are no medications that can effectively treat VPA-induced bone loss.Therefore,we constructed engineered small extracellular vesicles(E-sEVs)targeting osteoclast precursors in bone and naturally carrying anti-miR-6359 by introducing of EXOmotif(CGGGAGC)in the 3’-end of the anti-miR-6359 sequence.We confirmed that the E-sEVs exhibited decent bone/osteoclast precursor targeting and exerted protective therapeutic effects on VPA-induced bone loss,but not on ovariectomy(OVX)and glucocorticoid-induced osteoporotic models,deepening our understanding of the underlying mechanism and treatment strategies for VPA-induced bone loss.

关 键 词：MIR protective STIMULATION 

分 类 号：R68[医药卫生—骨科学]