Reactive oxygen species in tendon injury and repair

Reactive oxygen species (ROS) are chemical moieties that in physiological concentrations serve as fast-acting signaling molecules important for cellular homeostasis. However, their excess either due to overproduction or inability of the antioxidant system to inactivate them results in oxidative stress, contributing to cellular dysfunction and tissue damage.

In tendons, which are hypovascular, hypocellular, and composed predominantly of extracellular matrix (ECM), particularly collagen I, ROS likely play a dual role: regulating cellular processes such as inflammation, proliferation, and ECM remodeling under physiological conditions, while contributing to tendinopathy and impaired healing when dysregulated.

This review explores the sources of ROS in tendons, including NADPH oxidases and mitochondria, and their role in key processes such as tissue adaptation to mechanical load and injury repair, also in systemic conditions such as diabetes. In addition, we integrate the emerging perspective that calcium signaling—mediated by mechanically activated ion channels—plays a central role in tendon mechanotransduction under daily mechanical loads. We propose that mechanical overuse (overload) may lead to hyperactivation of calcium channels, resulting in chronically elevated intracellular calcium levels that amplify ROS production and oxidative stress. Although direct evidence linking calcium channel hyperactivity, intracellular calcium dysregulation, and ROS generation under overload conditions is currently circumstantial, this review aims to highlight these connections and identify them as critical avenues for future research.

By framing ROS within the context of both adaptive and maladaptive responses to mechanical load, this review provides a comprehensive synthesis of redox biology in tendon injury and repair, paving the way for future work, including development of therapeutic strategies targeting ROS and calcium signaling to enhance tendon recovery and resilience.