Collagen is the main source of extracellular support for multicellular animals. The mechanical strength of collagen fibrils depends on a highly regulated mechanism of intermolecular cross-linking. The basis of this cross-linking from the most primitive to the most advanced multicellular animals and across a diversity of vertebrate tissue types, is the formation of covalent bonds from aldehydes produced from lysyl and hydroxylysyl side-chains by lysyl oxidase. In the last decade it has become clear that such bonds form not only between collagen molecules of the same type in homopolymeric fibrils but also between different types of collagen molecule that have evolved to interact and form heteromeric structures. Furthermore, cross-linking amino acids and peptides containing them from collagen degradation, have received attention as bone resorption biomarkers in clinical studies and drug trials in the osteoporosis field. This review summarizes recent research directions with examples of advances in understanding complex interactions in cartilage collagen and the role of lysyl hydroxylase isoforms in regulating the pathway of cross-linking chemistry.
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