Zhang Yibo, Wu Yizhang, Wang Yong, Lu Jun, Lu Yang, Wang Peng, Li Lan, Yan Wenjin, Cai Hongling, Hannah Leigh Weisbecker, Zhang Lin, Bai Wubin, Jiang Qing, Xu Xingquan
State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
Department of Applied Physical Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
J Adv Res. 2025 Sep;75:505-520. doi: 10.1016/j.jare.2024.10.022. Epub 2024 Oct 21.
Achilles tendinopathy (AT) is a prevalent musculoskeletal disorder closely linked to oxidative stress. Existing evidence suggests a potential link between circadian clock rhythms and oxidative stress. However, the precise role of the circadian clock in the progression and treatment of AT remains unclear.
The purpose of this study was to investigate the role of the Achilles tendon circadian clock in AT pathology and explore the potential use of biomaterials for modulating the circadian clock in the treatment of AT.
We utilized in vivo and in vitro models to investigate the alterations of the circadian clock within the Achilles tendon during the progression of AT, as well as its impact on disease development. Additionally, we fabricated NbC@CeO composites featuring a Schottky heterojunction for regulating the circadian rhythm and validated its therapeutic efficacy and molecular mechanism of AT through both in vivo and in vitro experiments.
The Achilles tendon functioned as a peripheral oscillator with an independent and self-sustained time-keeping system. The rhythm of the Achilles tendon clock was disrupted during the development of AT, as indicated by the decreased amplitude of Bmal1 and Nrf2 rhythm expression. Mechanistically, the knockdown of Bmal1 disrupted the Achilles tendon clock, thereby destroying the Bmal1-Nrf2 axis dependent molecular defense mechanism, and exacerbating the inflammatory response, whereas overexpression of Bmal1 had a protective effect. NbC@CeO composites with Schottky heterojunctions enhance intercellular electrical signaling, boosting Bmal1 expression and mitigating AT's pathological changes. Importantly, enhancing Bmal1 expression during its peak, rather than its trough, was more effective.
This study identified the protective role of the circadian clock against oxidative stress and inflammation in the Achilles tendon. Achilles tendon circadian clock-targeted therapy represents a promising strategy for AT treatment.
跟腱病（AT）是一种常见的肌肉骨骼疾病，与氧化应激密切相关。现有证据表明昼夜节律与氧化应激之间存在潜在联系。然而，生物钟在AT进展和治疗中的具体作用仍不清楚。
本研究旨在探讨跟腱生物钟在AT病理中的作用，并探索生物材料在调节生物钟以治疗AT方面的潜在用途。
我们利用体内和体外模型研究AT进展过程中跟腱内生物钟的变化及其对疾病发展的影响。此外，我们制备了具有肖特基异质结的NbC@CeO复合材料来调节昼夜节律，并通过体内和体外实验验证其对AT的治疗效果和分子机制。
跟腱作为一个外周振荡器，具有独立且自我维持的计时系统。在AT发展过程中，跟腱生物钟的节律被打乱，表现为Bmal1和Nrf2节律表达幅度降低。机制上，敲低Bmal1会破坏跟腱生物钟，从而破坏依赖Bmal1-Nrf2轴的分子防御机制，加剧炎症反应，而Bmal1的过表达则具有保护作用。具有肖特基异质结的NbC@CeO复合材料增强细胞间电信号传导，提高Bmal1表达并减轻AT的病理变化。重要的是，在Bmal1表达峰值而非谷值时增强其表达更有效。
本研究确定了生物钟对跟腱氧化应激和炎症的保护作用。针对跟腱生物钟的治疗是一种有前景的AT治疗策略。
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