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Bone-targeting Engineered Small Extracellular Vesicles Carrying Anti-Mir-6359-cgggagc Prevent Valproic Acid-Induced Bone Loss

Signal Transduction and Targeted Therapy(2024)

Department of Orthopedics | Department of Clinical Laboratory | Division of Plastic Surgery | Medical Center of Trauma and War Injuries | Department of Plastic Surgery | Pingshan District People’s Hospital of Shenzhen

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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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要点】:本研究确认了VPA治疗与降低骨量和骨密度相关,并发现VPA通过增加osteoclast形成和活性导致骨丢失。创新性地,通过构建靶向osteoclast前驱细胞并自然携带抗miR-6359的工程化小外泌体,有效治疗VPA引起的骨丢失。

方法】:采用RNA测序、实时荧光定量PCR (qRT-PCR)、荧光原位杂交 (miR-6359-FISH)等技术研究VPA对osteoclast前驱细胞中miR-6359表达的影响。

实验】:使用工程化小外泌体 (E-sEVs) 靶向osteoclast前驱细胞,携带抗miR-6359-CGGGAGC序列,对VPA诱导的骨丢失具有保护性治疗效果,而对去势 (OVX) 和糖皮质激素诱导的骨质疏松模型无效。