Intermolecular cross-linking in fibrotic collagen

The extent, nature and location of the cross-links involved in the stabilization of collagen in fibrotic lesions are crucial to its subsequent removal, naturally or induced by treatment. Stabilization is achieved initially by divalent aldimine and keto-imine intermolecular cross-links located at the end-overlap region in the quarter-stagger alignment of the molecules in the fibre. Elucidation of the location of the cross-links also provides chemical evidence for the organization of the collagen molecule in the fibre. All the fibrous collagens are stabilized by these cross-links, the more stable keto-imine cross-link predominating in the types I and II collagens present in the initial stages of fibrosis. Further stabilization of the lesion usually follows, increasing the resistance to degradative enzymes, thus rendering the fibrosis irreversible. This maturation process, which also occurs in normal ageing, involves the formation of multivalent cross-links derived from the initial aldimine and keto-imine cross-links to form a three-dimensional network through a polymeric peptide (poly-alpha 1CB6 in type I collagen). The nature of these cross-links has not yet been elucidated. The so-called mature cross-link, 3-hydroxypyridinoline, could not be identified in this polymeric network. A secondary process involving non-enzymic glycosylation of lysine residues and subsequent intermolecular cross-linking has also been demonstrated, although the nature and extent of this type of cross-link remain to be determined.