Abstract
INTRODUCTION: 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. OBJECTIVE: 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. METHODS: 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 Nb(2)C@CeO(2) 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. RESULTS: 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. Nb(2)C@CeO(2) 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. CONCLUSION: 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.