Yang Qifan, Liu Jing, Liu Yanwei, Liu Shun, Wei Xiaokang, Yang Yilin, Zhang Weijie, Zhang Shuqi, Zhang Maosheng, Liu Bin, Wang Xinyu, Zhu Dong
Department of Orthopedic Traumatology, The First Hospital of Jilin University, Changchun, 130000, Jilin Province, PR China.
Gynecology and obstetrics, Jinan Maternity and Child Care Hospital Affiliated to Shandong First Medical University, Jinan, 250000, PR China.
Mater Today Bio. 2025 Jun 21;33:102009. doi: 10.1016/j.mtbio.2025.102009. eCollection 2025 Aug.
Obesity-induced osteoporosis is a prevalent complication among obese individuals. Conventional anti-osteoporosis medications often lack therapeutic specificity and may exacerbate lipid metabolism disorders. Consequently, identifying suitable pharmacological interventions for obesity-induced osteoporosis, elucidating its underlying biological mechanisms, and developing nanodrug delivery systems with enhanced biocompatibility and targeted delivery remain significant challenges.
This study reveals that the pathogenesis of obesity-induced osteoporosis is primarily driven by excessive mitophagy. Notably, Exendin-4 (Ex-4) has been shown to ameliorate mitophagy and mitigate obesity-induced osteoporosis. The nanocomposite DSPE-PEG-ALN (DPA)@Neutrophil membrane (NM)@Cu-TCPP(Zn)/Ex-4 (CTZE), characterized by high biocompatibility and reactive oxygen species (ROS) responsiveness, effectively targets bone tissue, reduces ROS levels, and regulates the release of Cu, Zn, Ex-4, and Alendronate (ALN). This composite interferes with B-cell lymphoma-2 (BCL2)- Beclin-1 (BECN1) binding via the tet methylcytosine dioxygenase 2 (TET2)/PTEN-induced putative kinase protein 1 (PINK1)/Parkin (E3 ubiquitin-protein ligase parkin) pathway, thereby promoting osteoblast differentiation and mineralization. The safety and efficacy of this nano-delivery platform were validated in a mouse model of obesity-induced osteoporosis.
In summary, our study illustrates that excessive mitophagy plays a crucial role in obesity-induced osteoporosis. Furthermore, DPA@NM@CTZE exhibits significant potential for the precise treatment of obesity-induced osteoporosis, mitigating the side effects of Ex-4, and enhancing the bone microenvironment.
肥胖诱导的骨质疏松症是肥胖个体中普遍存在的并发症。传统的抗骨质疏松药物通常缺乏治疗特异性，可能会加剧脂质代谢紊乱。因此，确定适合肥胖诱导骨质疏松症的药物干预措施，阐明其潜在的生物学机制，以及开发具有增强生物相容性和靶向递送功能的纳米药物递送系统仍然是重大挑战。
本研究表明，肥胖诱导骨质疏松症的发病机制主要由过度的线粒体自噬驱动。值得注意的是，艾塞那肽-4（Ex-4）已被证明可改善线粒体自噬并减轻肥胖诱导的骨质疏松症。具有高生物相容性和活性氧（ROS）响应性的纳米复合材料DSPE-PEG-ALN（DPA）@中性粒细胞膜（NM）@Cu-TCPP(Zn)/Ex-4（CTZE）有效地靶向骨组织，降低ROS水平，并调节铜、锌、Ex-4和阿仑膦酸盐（ALN）的释放。该复合材料通过四甲基胞嘧啶双加氧酶2（TET2）/PTEN诱导的假定激酶蛋白1（PINK1）/帕金（E3泛素蛋白连接酶帕金）途径干扰B细胞淋巴瘤-2（BCL2）-Beclin-1（BECN1）结合，从而促进成骨细胞分化和矿化。该纳米递送平台的安全性和有效性在肥胖诱导骨质疏松症的小鼠模型中得到验证。
总之，我们的研究表明过度的线粒体自噬在肥胖诱导的骨质疏松症中起关键作用。此外，DPA@NM@CTZE在精准治疗肥胖诱导的骨质疏松症、减轻Ex-4的副作用以及改善骨微环境方面具有显著潜力。
