Chang Wenju, Tian Bo, Qin Qin, Li Dongxiao, Zhang Yue, Zhou Chenmeng, Wu Bingbing, Zhang Mingchao, Shan Huajian, Ni Yichao, Dong Qirong, Wang Chao, Zhou Xiao-Zhong, Bai Jinyu
Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
Department of Orthopedics, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China.
ACS Nano. 2024 Dec 31;18(52):35368-35382. doi: 10.1021/acsnano.4c12064. Epub 2024 Dec 18.
The dynamic balance between bone resorption and formation is critical for maintaining healthy bone homeostasis. However, the receptor activator of the nuclear factor B ligand (RANKL) primarily stimulates mature osteoclasts to resorb bone, and its upregulation leads to osteoporosis in patients. Here, we designed RANK-expressing extracellular vesicles (EVs) derived from mesenchymal stem cells to maintain bone homeostasis in mice. This engineered EV (EV@R) effectively neutralizes excess RANKL in bone tissue due to the RANK-RANKL interaction, thereby attenuating osteoclast differentiation. Additionally, we found that miRNA-21a-5p in EV@R contributes to restoring bone metabolic homeostasis. We demonstrate the protective and therapeutic efficacy of EV@R against osteoporosis in the ovariectomy-induced osteoporosis mouse model with a lasting effect and minimal side effects. Our study provides an alternative way to use engineered EVs for bone homeostasis treatment.
骨吸收与骨形成之间的动态平衡对于维持健康的骨稳态至关重要。然而，核因子κB受体活化因子配体（RANKL）主要刺激成熟破骨细胞吸收骨，其上调会导致患者发生骨质疏松。在此，我们设计了源自间充质干细胞的表达RANK的细胞外囊泡（EVs），以维持小鼠的骨稳态。这种工程化的EV（EV@R）由于RANK-RANKL相互作用，可有效中和骨组织中过量的RANKL，从而减弱破骨细胞分化。此外，我们发现EV@R中的miRNA-21a-5p有助于恢复骨代谢稳态。我们在卵巢切除诱导的骨质疏松小鼠模型中证明了EV@R对骨质疏松的保护和治疗效果，具有持久作用且副作用最小。我们的研究提供了一种使用工程化EVs进行骨稳态治疗的替代方法。
