The Role of the Circadian Clock in Tendon Health and Tendinopathy

Introduction

Tendons, which connect muscles to bones, are prone to overuse injuries known as tendinopathy, affecting approximately 16.5 million people annually in the U.S. Despite being a significant clinical and socio-economic issue, the exact mechanisms behind tendinopathy remain unclear. Recent research suggests that the circadian clock, which regulates many biological processes in a 24-hour cycle, plays a crucial role in maintaining tendon health. Disruptions to this rhythm, such as those caused by shift work, have been linked to various diseases, including tendinopathy. Studies in mice have shown that mutations in circadian clock genes lead to tendon phenotypes resembling tendinopathy, highlighting the importance of circadian regulation in tendon homeostasis.

Circadian Regulation of Tendon Extracellular Matrix (ECM)

The extracellular matrix (ECM) of tendons, maintained by fibroblasts, is essential for tendon health. Research in mice has demonstrated that the tendon circadian clock regulates collagen secretion, with diurnal changes in collagen fibril structure and viscoelastic properties. These changes, termed the “chronomatrix,” suggest that tendon ECM undergoes daily fluctuations. Human tendons also exhibit circadian rhythms, with tenocytes showing endogenous circadian rhythms and reduced stiffness in the evening. However, it remains unclear whether these circadian patterns are disrupted in chronic tendinopathy.

Study Objectives and Methods

This study aimed to investigate time-dependent circadian gene expression in human patellar tendons and determine if these patterns are altered in chronic tendinopathy. Patellar tendon biopsies were taken from healthy individuals and those with chronic tendinopathy at two time points, 12 hours apart. RNA sequencing (RNAseq) and RT-qPCR were used to analyze gene expression, while transmission electron microscopy (TEM) and hydroxyproline assays assessed collagen fibril diameter and acid-soluble collagen content, respectively.

Key Findings

1. Circadian Gene Expression in Healthy Tendons: The study identified 280 genes with time-dependent expression in healthy tendons, including 11 conserved circadian clock genes. These genes exhibited diurnal fluctuations, with some peaking during the day and others at night. This confirms that human tendons have a functional circadian clock.
2. Collagen Expression and ECM Changes: Collagen I expression was higher during the day, suggesting that collagen synthesis may be influenced by daily activity levels. However, no significant diurnal changes in acid-soluble collagen or fibril diameter were observed in human tendons, unlike in mice.
3. Disrupted Circadian Rhythm in Tendinopathy: In chronic tendinopathy, the expression of circadian clock genes was significantly reduced, and the diurnal variation in collagen I expression was lost. This suggests that the circadian rhythm is disrupted in tendinopathic tendons, potentially contributing to disease progression.
4. Contralateral Tendons: Even in the non-affected tendons of patients with chronic tendinopathy, there were signs of disrupted circadian gene expression and collagen turnover, indicating that these changes may precede clinical symptoms.

Discussion

The findings highlight the importance of the circadian clock in maintaining tendon health and suggest that its disruption may contribute to the development of tendinopathy. The loss of diurnal variation in collagen expression and circadian gene activity in tendinopathic tendons points to a potential breakdown in tendon homeostasis. While the exact cause-effect relationship remains unclear, the data suggest that restoring circadian rhythms could be a therapeutic strategy for treating tendinopathy.

Clinical Implications

The body’s internal clock is a powerful yet often overlooked factor in injury prevention and recovery. By aligning training, sleep, nutrition, and recovery practices with natural circadian rhythms, individuals can optimize tissue repair, reduce injury risk, and enhance overall performance. 

Pharmacological interventions that target circadian rhythms, such as glucocorticoids, which synchronize circadian oscillators, could be explored for their potential to restore tendon homeostasis and alleviate tendinopathy symptoms.

Conclusion

The study provides the first evidence of time-dependent circadian gene expression in human tendons and its disruption in chronic tendinopathy. The findings underscore the importance of circadian regulation in tendon health and suggest that targeting the circadian clock could be a promising approach for preventing and treating tendon overuse injuries. Further research is needed to explore the mechanisms linking circadian rhythms to tendon pathology and to develop effective therapeutic interventions.