2. Academic Validation
  3. Bone-targeting engineered small extracellular vesicles carrying anti-miR-6359-CGGGAGC prevent valproic acid-induced bone loss

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

  • Signal Transduct Target Ther. 2024 Jan 22;9(1):24. doi: 10.1038/s41392-023-01726-8.
Xudong Xie # 1 2,  Peng Cheng # 1 2,  Liangcong Hu # 1 2,  Wu Zhou # 1 2,  Detai Zhang # 3,  Samuel Knoedler 4 5,  Guodong Liu 6,  Yuan Xiong 1 2,  Hang Xue 1 2,  Yiqiang Hu 1 2,  Barbara Kern 7 8,  Doha Obed 4 9,  Adriana C Panayi 4 10,  Lang Chen 1 2,  Chenchen Yan 1 2,  Ze Lin 1 2,  Guandong Dai 11,  Bobin Mi 12 13,  Yingze Zhang 14 15,  Guohui Liu 16 17
Affiliations

Affiliations

  • 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 Charité Mitte
  • 8
  • 9 Berlin Institute of Health, Charité - Universitätsmedizin Berlin, Berlin, Germany.
  • 10 Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
  • 11 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.
  • 12 Pingshan District People's Hospital of Shenzhen, Pingshan General Hospital of Southern Medical University, Shenzhen, Guangdong, 518118, China.
  • 13 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. mibobin@hust.edu.cn.
  • 14 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China. mibobin@hust.edu.cn.
  • 15 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. drzhangyz@126.com.
  • 16 Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, NO.139 Ziqiang Road, Shijiazhuang, 050051, China. drzhangyz@126.com.
  • 17 Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. liuguohui@hust.edu.cn.
  • 18 Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China. liuguohui@hust.edu.cn.
  • # Contributed equally.
PMID: 38246920 DOI: 10.1038/s41392-023-01726-8
Abstract

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.

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