Enzymic and non‐enzymic cross‐linking mechanisms in relation to turnover of collagen: relevance to aging and exercise

Abstract

The molecular mechanisms involved in the aging of collagen and consequent increase in mechanical strength and stiffness occur in a series of enzymic and non-enzymic intermolecular cross-links. The enzymic mechanism involves divalent aldimine intermolecular cross-links derived from the reaction of aldehydes which then mature to trivalent cross-links and further stabilize the collagen fiber and is now well known. Recent studies have demonstrated that the rate of turnover and level of telopeptide lysyl hydroxylation modifies the nature of the cross-link and hence the mechanical strength of the fiber. The slow turnover of mature collagen subsequently allows accumulation of the products of the adventitious non-enzymic reaction of glucose with the lysines in the triple helix to form glucosyl lysine and its Amadori product, that is, the Maillard reaction. These products are subsequently oxidized to a complex series of advanced glycation end-products, some of which are intermolecular cross-links between the triple helices rendering the fiber too stiff for optimal functioning of the collagen fibers, and consequently of the particular tissue involved. The glycation reactions following maturation are true aging processes, and attempts at their specific inhibition involve competitive inhibition of the Maillard reaction and chemical cleavage of the glycation cross-links. It is clear that the nature of the age-related cross-links and hence tissue strength depends on the rate of turnover of the collagen. An examination of the particular effect of strenuous exercise on the rate of turnover of collagen and hence cross-linking in different tissues could lead to a better understanding of optimal sports training regimes.

Collagen and mineral deposition in rabbit cortical bone during maturation and growth: Effects on tissue properties

“…17 However, we did not determine other cross-links in connective tissues, such as pyrrolic crosslinks, MODIC, GODIC, DOGDIC, or glucosepane. 11,35,36 A limitation of our study is that due to the highly varying size of the specimens, all variables could not be kept constant between age groups during mechanical testing (Fig. 1).…”

The fracture mechanics of human bone: influence of disease and treatment

“…82,83 The fibrils (80-100 nm diameter 1 ) are surrounded by polycrystalline extrafibrillar mineral platelets (5 nm thickness, 50-80 nm width and 40-200 nm length 3 ); the extrafibrillar as well as the intrafibrillar matrix may also contain molecular components, such as non-collagenous proteins or cross-links, promoting the formation of sacrificial bonds. 5,9,15,16,84 In the fibrils, type I collagen molecules (1.5 nm diameter, 300 nm length) and hydroxyapatite nanocrystals (50 nm width, 25 nm height, 1.5-4 nm thickness) form a composite structure, where arrays of collagen molecules staggered at 67 nm are embedded with nanoplatelets of hydroxyapatite mineral. 1 Adapted from Zimmermann et al and Milovanovic et al 45,82 The fracture mechanics of human bone EA Zimmermann et al another extrinsic mechanism occurring when a crack encounters an interface in the bone, such as the highly mineralized cement lines at the outer boundary of the osteons or the modulating mechanical properties of the lamellae (Figures 3c and d).…”

“…7 These cross-links also known as advanced glycation end-products form through a glucose-mediated reaction and may form both intra-and interfibrillar connections. 8,9 The mineralized collagen fibrils hierarchically assemble into lamellae to form osteons, which are the most prominent motif on the microstructural scale ( Figure 1). The osteons are cylindrical with a nominal circular cross-section and a central vascular channel called the Haversian canal.…”

Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue

“…Avery and Bailey [29] have postulated that NEG crosslinking is an age-related process, at least in slowly metabolizing collagenous tissues. They reason that the slow turnover of mature collagen (i.e., slower than the rate of bone remodeling) allows for a continual accumulation of advanced glycation end-products (AGE) as glucose reacts with numerous side-chains in the triple helix of collagen, namely those associated with lysine and arginine.…”