Abstract
Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified. Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties (p<0.05). The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone.
Highlights
Non-traumatic skeletal fractures are directly related to increased incapacitation, morbidity, and mortality and pose a serious health problem to an aging population [1,2,3]
There was no clear correlation between the amount of advanced glycation end-products (AGEs) reduction and phenacylthiazolium bromide (PTB) treatment concentration, but the seven day treatment resulted in a greater reduction of AGEs than the three day treatment
Phenacylthiazolium Bromide to improve the quality of existing bone matrix by cleaving established AGE crosslinks known to accumulate with aging, disease, and the anti-resorptive treatment of osteoporosis
Summary
Non-traumatic skeletal fractures are directly related to increased incapacitation, morbidity, and mortality and pose a serious health problem to an aging population [1,2,3]. Several age-related changes in bone morphology and composition have been identified and were subsequently linked to an increased risk of non-traumatic fracture [4,5,6,7]. AGEs are a series of post-translational modifications in the cross-link profile of long-lived proteins throughout the body [11]. These modifications are caused by the reaction of reducing sugars found in the extracellular space with amino groups of collagen through a process called non-enzymatic glycation (NEG). The resulting covalent, glucose-derived protein crosslinks are naturally occurring and can be replicated in-vitro by subjecting collagen to reducing sugars in solution [12]
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