Role of the tendon circadian clock in tendinopathy and implications for therapeutics

Abstract

Tendinopathy or tendon overuse injury is a major clinical problem for individuals and has a significant socio-economic cost. Its pathophysiology is not yet fully understood and involves multiple factors, including mechanical, cellular and molecular factors. The circadian rhythm has been shown to be a major regulator of extracellular matrix (ECM) homeostasis in several connective tissues, including tendon. Very recently, the human patellar tendon has been established as a peripheral clock tissue that exhibits dampening with chronic tendinopathy, and this has important translational and clinical relevance. This review summarises what is currently known about the role of the tendon circadian clock in collagen and tendon ECM homeostasis and proposes a role for circadian clock disruption in tendinopathy. A better understanding of the mechanisms that regulate tendon clock synchronisation could guide the development of new therapeutic strategies for managing tendon overuse injuries.

Keywords: circadian clock; collagen; extracellular matrix; tendinopathy; tendon; tissue homeostasis; translational medicine.

FIGURE 1

Graphical overview of circadian clock‐regulated homeostatic processes in tendon. Tendon is a peripheral tissue clock. The endogenous circadian rhythm regulates the expression of tendon‐specific CCGs, which control collagen secretion, chronomatrix turnover and ECM homeostasis. Tendon CCGs responsible are noted in brackets. The tendon circadian rhythm can be synchronised using glucocorticoids and is dampened with ageing. Collagen I expression is responsive to exercise, but whether there is any crosstalk between exercise and the tendon clock, and whether there is any negative feedback from inactivity are currently unknown. Figure created using BioRender.