Multiscale mechanical effects of native collagen cross-linking in tendon

Abstract

The hierarchical structure of tendon allows for attenuation of mechanical strain down decreasing length scales. While reorganization of collagen fibers accounts for microscale strain attenuation, cross-linking between collagen molecules contributes to deformation mechanisms at the fibrillar and molecular scales. Divalent and trivalent enzymatic cross-links form during the development of collagen fibrils through the enzymatic activity of lysyl oxidase (LOX). By establishing connections between telopeptidyl and triple-helical domains of adjacent molecules within collagen fibrils, these cross-links stiffen the fibrils by resisting intermolecular sliding. Ultimately, greater enzymatic cross-linking leads to less compliant and stronger tendon as a result of stiffer fibrils. In contrast, nonenzymatic cross-links such as glucosepane and pentosidine are not produced during development but slowly accumulate through glycation of collagen. Therefore, these cross-links are only expected to be present in significant quantities in advanced age, where there has been sufficient time for glycation to occur, and in diabetes, where the presence of more free sugar in the extracellular matrix increases the rate of glycation. Unlike enzymatic cross-links, current evidence suggests that nonenzymatic cross-links are at least partially isolated to the surface of collagen fibers. As a result, glycation has been proposed to primarily impact tendon mechanics by altering molecular interactions at the fiber interface, thereby diminishing sliding between fibers. Thus, increased nonenzymatic cross-linking decreases microscale strain attenuation and the viscous response of tendon. In conclusion, enzymatic and nonenzymatic collagen cross-links have demonstrable and distinct effects on the mechanical properties of tendon across different length scales.

Transverse tendon stiffness is reduced in people with Achilles tendinopathy: A cross-sectional study

“…In addition to injury, which leads to a pathological loss of tendon stiffness,[26] exercise can lead to an adaptive increase in tendon stiffness [2]. The mechanisms by which tendon stiffness increases in response to execise are not fully understood, but may involve a combination of new collagen fibre formation [27] and increased density of cross-links [28]. Longterm exercise habits are also capable of inducing changes in tendon cross-sectional area [29].…”

An Inducible Model for Unraveling the Effects of Advanced Glycation End-Product Accumulation in Aging Connective Tissues

“…Despite ample correlative evidence connecting AGEs to tissue injury [44,45], degeneration [23,26], and multiple chronic diseases, such as cardiovascular disease [17], chronic kidney disease [18], diabetes [46], Alzheimer's and Parkinson's disease [22], little is known how AGEs impact matrix mechanics and cell-matrix interactions, resulting in limited therapeutic options. One reason for this limited understanding is because AGES are typically induced using concentrations of ribose greater than 200 mM, which decrease cell viability and make it impossible to investigate cellmatrix interactions [7,9,10]. Here, we induced native levels of AGEs with lower concentrations of ribose and maintained cell viability through 15 days of culture.…”

“…AGEs can either crosslink proteins, directly altering their structure and in-turn altering their properties and function, or alter binding sites on proteins changing cellular signaling [12]. Despite ample correlative evidence connecting collagen glycation to aging and disease, little is known how AGEs impact matrix mechanics and cell-matrix interactions, resulting in limited therapeutic options [9,10]. It is difficult to study the AGE mechanism in vivo due to differences in collagen organization, disease state, and age [9,10].…”

“…Despite ample correlative evidence connecting collagen glycation to aging and disease, little is known how AGEs impact matrix mechanics and cell-matrix interactions, resulting in limited therapeutic options [9,10]. It is difficult to study the AGE mechanism in vivo due to differences in collagen organization, disease state, and age [9,10]. In vitro models are an attractive means to study AGEs because they eliminate confounding variables of disease state, lifestyle, and age.…”

“…Ribose is typically used to induce AGEs in experiments due to its higher reactivity rate, in comparison to glucose and fructose, which ultimately shortens the timeframe needed for AGE formation to occur [29,30]. However, in vitro work is often performed with concentrations greater than 200 mM ribose, resulting in superphysiological levels of glycation and low cell viability [7,10,28]. Due to low cell viability in these systems it is impossible to study the cellular response to AGE protein modifications, which in turn greatly reduces the physiological reliability of the results.…”