Kračun Damir, Görlach Agnes, Snedeker Jess G, Buschmann Johanna
Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, Sternwartstrasse 14, 8091, Zurich, Switzerland; University Clinic Balgrist, Orthopaedic Biomechanics, Forchstrasse 340, 8008, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Gloriastrasse 37/39, 8092, Zurich, Switzerland.
Experimental and Molecular Paediatric Cardiology, German Heart Centre Munich, TUM University Hospital, Technical University of Munich, Munich, 80636, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
Redox Biol. 2025 Apr;81:103568. doi: 10.1016/j.redox.2025.103568. Epub 2025 Feb 25.
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.
活性氧（ROS）是一类化学基团，在生理浓度下作为对细胞内稳态至关重要的快速作用信号分子。然而，由于其产生过多或抗氧化系统无法使其失活，导致ROS过量，从而引发氧化应激，进而导致细胞功能障碍和组织损伤。肌腱血管少、细胞少，主要由细胞外基质（ECM）组成，尤其是I型胶原蛋白，ROS可能在其中发挥双重作用：在生理条件下调节细胞过程，如炎症、增殖和ECM重塑，而当调节失调时则会导致肌腱病和愈合受损。本综述探讨了肌腱中ROS的来源，包括NADPH氧化酶和线粒体，以及它们在组织适应机械负荷和损伤修复等关键过程中的作用，还涉及糖尿病等全身性疾病中的作用。此外，我们整合了新出现的观点，即由机械激活离子通道介导的钙信号在日常机械负荷下的肌腱机械转导中起核心作用。我们提出，机械过度使用（过载）可能导致钙通道过度激活，导致细胞内钙水平长期升高，从而放大ROS产生和氧化应激。尽管目前在过载条件下将钙通道过度活跃、细胞内钙调节失调和ROS产生联系起来的直接证据是间接的，但本综述旨在强调这些联系，并将它们确定为未来研究的关键途径。通过将ROS置于对机械负荷的适应性和适应不良反应的背景下，本综述全面综合了肌腱损伤和修复中的氧化还原生物学，为未来的工作铺平了道路，包括开发针对ROS和钙信号的治疗策略，以增强肌腱恢复能力和弹性。
