Glycosaminoglycan-Mediated Fibril Sliding and its Role in Fatigue-Induced Microdamage and Rupture in Aged and Healing Achilles Tendons
While collagen contributes most of the tendon dry weight, many other small matrix proteins regulate important structure-function mechanisms. Glycosaminoglycans (GAGs) reside in the tendon ECM on proteoglycan core proteins such as decorin and biglycan, which constitute a small percentage of the tissue’s dry weight. As a negatively charged polysaccharide, GAGs can bind to water molecules to modulate tissue hydration, lubrication, and friction between neighboring structures in many musculoskeletal tissues, including tendon. While GAGs are present throughout tendon, areas of high GAG concentration are often in regions of the tendon that undergo compression, such as the tendon insertion to bone. However, the relative amount of GAGs in tendons with these compressed insertion regions declines with age. While GAGs may not play a direct prominent role in elastic mechanics, they have been postulated to promote fibril sliding by retaining water and increasing fibril spacing and lubrication. This also indicates that they provide an important load-bearing mechanism in tissues with aligned fibrils. Further, this sliding mechanism may reduce fibril stress and thus protect against repetitive, viscoelastic processes that cause tendon damage, namely fatigue. Yet, the role of GAGs in fatigue rupture remains unelucidated. The goal of this work is to define the multiscale interplay between GAGs, interfibrillar load transmission, and fatigue injury in intact and healing mature and aged tendons. Our experiments will leverage chondroitinase digestion to test tendons after removal of GAGs. Tendons from mice at different ages and different healing stages will be rigorously assessed using multiscale mechanical testing, biochemical compositional analysis, and various imaging modalities to determine the impact of GAGs on tendon structure-function. These studies will elucidate the role of GAGs in preventing microdamage and eventual rupture in Achilles tendons undergoing fatigue loading. Further, these studies will enhance our understanding of mechanisms that lead to injury in aging and healing tendons and enhance therapeutic strategies preceding tendon injury.