Non-AGE collagen crosslinks

While advanced glycation end-products (AGEs) are one well-known source of collagen crosslinks, a distinct class of enzyme-mediated crosslinks is introduced by lysyl oxidase (LOX) and its paralogues (LOXL1–4), copper-dependent amine oxidases that oxidise specific lysine and hydroxylysine residues in newly secreted collagen and elastin to reactive aldehydes, which then condense spontaneously to form covalent intramolecular and intermolecular crosslinks such as pyridinoline and deoxypyridinoline. LOX-mediated crosslinking is essential for tensile strength and tissue integrity during development, but pathological upregulation — driven by TGF-beta, hypoxia, and PDGF signalling in fibrotic and tumour microenvironments — produces excessive matrix stiffness that drives fibrosis, impairs cellular mechanosensing, and promotes tumour invasion. Unlike AGE crosslinks, LOX-mediated bonds are in principle modifiable by LOX inhibitors such as beta-aminopropionitrile (BAPN), making this pathway a pharmacological target distinct from the AGE/RAGE axis.