Mao Min-Zhi, Zheng Ming-Hui, Guo Bei, Ling Ya-Li, Lin Xiao, Li Fu-Xing-Zi, Shan Su-Kang, Dai De-Xing, Qiu Lei, Cai Xue-Yang, Ding Ya, Gu Ying-Ying, Deng Qi-Rong, Zhou Zhi-Ang, Lei Li-Min, Tao Cheng, Cui Rong-Rong, Wu Feng, Zhang Fei, Wu Bo, Liao Le-Le, Tan Chang-Ming, Liao Xiao-Bo, Yuan Ling-Qing, Xu Feng
Department of Orthopedics, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
J Nanobiotechnology. 2025 Jul 12;23(1):504. doi: 10.1186/s12951-025-03587-5.
Exercise maintains bone health and produces protective effects on bone loss. In this study, we investigated the potential protective effects of circulating small extracellular vesicles (sEVs) generated under endurance exercise training (Exe-sEVs) on ovariectomized (OVX)-induced bone loss. Inhibition of sEVs secretion by GW4869 partially reversed exercised-induced protection against OVX-induced bone loss. Importantly, Exe-sEVs was internalized by bone tissue and alleviated bone loss in OVX-mice. The increased levels of fibronectin type-III domain-containing protein 5 (FNDC5/irisin) in Exe-sEVs contributed to the promotion of osteogenesis in bone marrow mesenchymal stem cells (BM-MSCs). However, systemic knockdown of FNDC5, the precursor of irisin, abolished the exercise-induced protective effects against bone loss in OVX-mice. Moreover, incubation of irisin enhanced osteogenesis and attenuated adipogenesis in BM-MSCs. Intriguingly, implantation of BM-MSCs overexpressing FNDC5 accelerated osteogenesis and chondrogenesis in BALB/c immunodeficiency mice. Mechanistically, irisin promoted phosphorylation of p38MAPK and JNK, but not ERK. Blocking the JNK and p38MAPK signaling pathway with specific inhibitors abolished the pro-osteogenesis and anti-adipogenesis effects of irisin on BM-MSCs. However, inhibition of β-arrestin-2 rescued the irisin-induced activation of p38MAPK and JNK. Finally, aptamer-modified FNDC5-sEVs (Apt-FNDC5-sEVs) exhibited higher enrichment in bone tissues and enhanced bone formation. In conclusion, exercise-induced circulating FNDC5/irisin-enriched sEVs promote osteogenesis of mouse BM-MSCs both in vitro and in vivo, partially through a β-arrestin-2-dependent p38MAPK and JNK signaling pathway. Apt-FNDC5-sEVs represent a promising strategy for the treatment of osteoporosis.
运动可维持骨骼健康，并对骨质流失产生保护作用。在本研究中，我们调查了耐力运动训练产生的循环小细胞外囊泡（Exe-sEVs）对去卵巢（OVX）诱导的骨质流失的潜在保护作用。GW4869对sEVs分泌的抑制部分逆转了运动诱导的对OVX诱导的骨质流失的保护作用。重要的是，Exe-sEVs被骨组织内化，并减轻了OVX小鼠的骨质流失。Exe-sEVs中含III型纤连蛋白结构域蛋白5（FNDC5/鸢尾素）水平的升高有助于促进骨髓间充质干细胞（BM-MSCs）的成骨作用。然而，鸢尾素前体FNDC5的全身敲低消除了运动诱导的对OVX小鼠骨质流失的保护作用。此外，鸢尾素的孵育增强了BM-MSCs的成骨作用并减弱了其脂肪生成。有趣的是，植入过表达FNDC5的BM-MSCs加速了BALB/c免疫缺陷小鼠的成骨作用和软骨生成。机制上，鸢尾素促进p38MAPK和JNK的磷酸化，但不促进ERK的磷酸化。用特异性抑制剂阻断JNK和p38MAPK信号通路消除了鸢尾素对BM-MSCs的促成骨和抗脂肪生成作用。然而，抑制β-抑制蛋白2可挽救鸢尾素诱导的p38MAPK和JNK的激活。最后，适体修饰的FNDC5-sEVs（Apt-FNDC5-sEVs）在骨组织中表现出更高的富集，并增强了骨形成。总之，运动诱导的循环富含FNDC5/鸢尾素的sEVs在体外和体内均促进小鼠BM-MSCs的成骨作用，部分是通过β-抑制蛋白2依赖性p38MAPK和JNK信号通路。Apt-FNDC5-sEVs代表了一种有前景的骨质疏松症治疗策略。
