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Concurrent with a progressive loss of regenerative capacity, connective tissue aging is characterized by a progressive accumulation of Advanced Glycation End-products (AGEs). Besides being part of the typical aging process, type II diabetics are particularly affected by AGE accumulation due to abnormally high levels of systemic glucose that increases the glycation rate of long-lived proteins such as collagen. Although AGEs are associated with a wide range of clinical disorders, the mechanisms by which AGEs contribute to connective tissue disease in aging and diabetes are still poorly understood. The present study harnesses advanced multiscale imaging techniques to characterize a widely employed in vitro model of ribose induced collagen aging and further benchmarks these data against experiments on native human tissues from donors of different age. These efforts yield unprecedented insight into the mechanical changes in collagen tissues across hierarchical scales from molecular, to fiber, to tissue-levels. We observed a linear increase in molecular spacing (from 1.45 nm to 1.5 nm) and a decrease in the D-period length (from 67.5 nm to 67.1 nm) in aged tissues, both using the ribose model of in vitro glycation and in native human probes. Multiscale mechanical analysis of in vitro glycated tendons strongly suggests that AGEs reduce tissue viscoelasticity by severely limiting fiber-fiber and fibril-fibril sliding. This study lays an important foundation for interpreting the functional and biological effects of AGEs in collagen connective tissues, by exploiting experimental models of AGEs crosslinking and benchmarking them for the first time against endogenous AGEs in native tissue.

Shoulders with supraspinatus (SSP) tears are associated with significantly larger critical shoulder angles (CSA) compared to disease-free shoulders. We hypothesized that larger CSAs increase the ratio of joint shear to joint compression forces (defined as "instability ratio"), requiring substantially increased compensatory supraspinatus loads. A shoulder simulator with simulated deltoid, supraspinatus, infraspinatus/teres minor, and subscapularis musculotendinous units was constructed. The model was configured to represent either a normal CSA of 33˚or a CSA characteristic of shoulders with rotator cuff tears (38˚), and the components of the joint forces were measured. The instability ratio increased for the 38˚CSA compared with the control CSA (33˚) for a range of motion between 6˚to 61˚of thoracohumeral abduction with the largest differences in instability observed between 33˚and 37˚of elevation. In this range, SSP force had to be increased by 13-33% (15-23 N)

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Evidence against proteoglycan mediated collagen fibril load transmission and dynamic viscoelasticity in tendon Fessel, G; Snedeker, J G Fessel, G; Snedeker, J G (2009 The glycosaminoglycan (GAG) dermatan sulphate and chondroitin sulphate side-chains of small leucine-rich proteoglycans have been increasingly posited to act as molecular cross links between adjacent collagen fibrils and to directly contribute to tendon elasticity. GAGs have also been implicated in tendon viscoelasticity, supposedly affecting frictional loss during elongation or fluid flow through the extra cellular matrix.The current study sought to systematically test these theories of tendon structure-function by investigating the mechanical repercussions of enzymatic depletion of GAG complexes by chondroitinase ABC in a reproducible tendon structure-function model (rat tail fascicles). The extent of GAG removal (at least 93%) was verified by relevant spectrophotometric assays and transmission electron microscopy. Dynamic viscoelastic tensile tests on GAG depleted rat tail tendon fascicle were not mechanically different from controls in storage modulus (elastic behavior) over a wide range of strain-rates (0.05, 0.5, and 5% change in length per second) in either the linear or nonlinear regions of the material curve. Loss modulus (viscoelastic behavior) was only affected in the nonlinear region at the highest strain rate, and even this effect was marginal (19% increased loss modulus, p=0.035). Thus glycosaminoglycan chains of small leucine rich proteoglycans do not appear to mediate dynamic elastic behavior nor do they appear to regulate the dynamic viscoelastic properties in rat tail tendon fascicles.

SummaryThe non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity. This focused review will summarize what is currently known regarding collagen glycation as a potential driver of connective tissue disease. We concentrate attention on tendon as an affected connective tissue with large clinical relevance, and as a tissue that can serve as a useful model tissue for investigation into glycation as a potentially critical player in tissue fibrosis related to ageing and diabetes.