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 — pyridinoline and deoxypyridinoline in collagen, and desmosine and isodesmosine in elastin. 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.