Tong Xianqin, Liu Minchao, Li Jiao, Zhang Weihua, Hu Rong, Yang Gang, Deng Jiajia, Li Yuanyuan, Li Xiaomin, Liu Yuehua
Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai 201100, China.
Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai 201100, China.
Natl Sci Rev. 2025 May 27;12(7):nwaf214. doi: 10.1093/nsr/nwaf214. eCollection 2025 Jul.
Muscle and bone have intimate biochemical associations spatiotemporally. Yet, the muscle-bone dynamic alterations under intermittent hypoxia (IH) remain unclear, primarily due to the lack of suitable microphysiological models. Herein, we developed a novel musculoskeletal organoids-on-chip (MSK OoC), advancing an integrated study of muscle-bone biochemical communication and personalized interventional strategies. Within this MSK OoC, muscle organoids (MOs) replicate micro-architecture, while bone organoids mimic both the formation and remodeling processes. Utilizing MSK OoC, we discovered that IH-induced muscle pathology suppressed osteogenesis but stimulated osteoclastogenesis. The mitochondria protein Sirt3 in muscle played a pivotal role in regulating bone metabolism via myokine Cxcl5. Besides, mitochondria-targeting sequence-mediated Sirt3 overexpression in MOs effectively reversed bone deterioration. To validate mitochondria-targeted therapeutics, a Janus silica nano-vehicle was adopted to deliver resveratrol upon MSK OoC, effectively rescuing the pathological muscle-bone dysfunction. This study highlights the potential of the MSK OoC platform for investigating interorgan communication and developing precise nanomedicine therapies.
肌肉和骨骼在时空上有着密切的生化联系。然而，间歇性缺氧（IH）下肌肉与骨骼的动态变化仍不清楚，这主要是由于缺乏合适的微生理模型。在此，我们开发了一种新型的肌肉骨骼类器官芯片（MSK OoC），推动了对肌肉-骨骼生化通讯和个性化干预策略的综合研究。在这个MSK OoC中，肌肉类器官（MOs）复制微观结构，而骨类器官则模拟形成和重塑过程。利用MSK OoC，我们发现IH诱导的肌肉病变抑制了成骨作用，但刺激了破骨细胞生成。肌肉中的线粒体蛋白Sirt3通过肌动蛋白Cxcl5在调节骨代谢中起关键作用。此外，线粒体靶向序列介导的MOs中Sirt3过表达有效逆转了骨退化。为了验证线粒体靶向治疗，采用了一种Janus二氧化硅纳米载体在MSK OoC上递送白藜芦醇，有效挽救了病理性肌肉-骨骼功能障碍。这项研究突出了MSK OoC平台在研究器官间通讯和开发精确纳米医学疗法方面的潜力。
