REGULATORS OF COLLAGEN CROSSLINKING IN DEVELOPING AND ADULT TENDONS

Tendons are collagen-rich musculoskeletal tissues that possess the mechanical strength needed to transfer forces between muscles and bones. The mechanical development and function of tendons are impacted by collagen crosslinks. However, there is a limited understanding of how collagen crosslinking is regulated in tendon during development and aging. Therefore, the objective of the present review was to highlight potential regulators of enzymatic and non-enzymatic collagen crosslinking and how they impact tendon function. The main collagen crosslinking enzymes include lysyl oxidase (LOX) and the lysyl oxidase-like isoforms (LOXL), whereas non-enzymatic crosslinking is mainly mediated by the formation of advanced glycation end products (AGEs). Regulators of the LOX and LOXL enzymes may include mechanical stimuli, mechanotransducive cell signaling pathways, sex hormones, transforming growth factor (TGF)beta family, hypoxia, and interactions with intracellular or extracellular proteins. AGE accumulation in tendon is due to diabetic conditions and aging, and can be mediated by diet and mechanical stimuli. The formation of these enzymatic and non-enzymatic collagen crosslinks plays a major role in tendon biomechanics and in the mechanisms of force transfer. A more complete understanding of how enzymatic and non-enzymatic collagen crosslinking is regulated in tendon will better inform tissue engineering and regenerative therapies aimed at restoring the mechanical function of damaged tendons.

Automated summary

This review focuses on the regulatory mechanisms of collagen crosslinking in tendons. Enzymatic crosslinking is mainly regulated by lysyl oxidase (LOX) and lysyl oxidase-like isoforms (LOXL), while non-enzymatic crosslinking is mediated by the formation of advanced glycation end products (AGEs). Factors that regulate the activity of LOX and LOXL enzymes include mechanical stimuli, cell signaling pathways, sex hormones, hypoxia, and interactions with intracellular or extracellular proteins. Accumulation of AGEs in tendons is associated with diabetic conditions and aging, and can be influenced by diet and mechanical stimuli. Understanding the regulation of enzymatic and non-enzymatic collagen crosslinking in tendons is crucial for tissue engineering and regenerative therapies aimed at restoring damaged tendon function.