Role of serum advanced glycation end-products in altering tendon properties with diabetes

PROJECT SUMMARY Impaired tendon biomechanical function reduces mobility and quality of life for the majority of the ~30 million Americans with diabetes, resulting in a substantial economic burden to these individuals and society. Any new approach to enhancing tendon function in people with diabetes is hindered by a poor understanding of the underlying etiology of impaired tendon biomechanical properties. Critically, the role that various serum factors play in the development of tendon complications in individuals with diabetes remains unclear. Our multidisciplinary research team hypothesizes that increased serum advanced glycation end-products (AGEs), with subsequent activation of receptors for AGEs (RAGE), is a principal mechanism driving tendon complications with diabetes. Specifically, activation of RAGE impairs tenocyte function resulting in loss of collagen fibril organization and subsequent impairment of biomechanical function. AGEs accumulate in the serum of patients with diabetes. Our preliminary cell culture work shows that treating tendon-derived cells with AGEs, which cannot form collagen crosslinks, adversely affects critical aspects of tendon ECM maintenance. We have also found that AGEs promote an environment favoring tendon ECM degradation. Utilizing human subjects, we demonstrate that increasing serum AGE concentrations are associated with declining tendon biomechanical properties (e.g., modulus). Serum AGEs can interact with RAGE to promote inflammation and oxidative stress, but such a connection to changes in tendon ECM organization and biomechanical function impairment has not been established. This project aims to 1) delineate the role of serum AGEs and activation of RAGE in promoting tendon ECM disorganization and impairment of biomechanical properties and 2) determine the relationship of serum AGEs to in vivo tendon biomechanical properties and in vivo indicators of tendon collagen fibril organization. Filling these gaps will promote new approaches for improving tendon function and reducing this challenging clinical condition's economic and social burden. Using a mouse model with an inducible RAGE deletion and a model of type 2 diabetes, we will assess the effects of chronically elevated serum AGEs on tendon ECM organization and biomechanical function and the involvement of RAGE in this process. We will use novel ultrasound and magnetic resonance imaging (MRI) methods to determine the relationships between serum AGE concentrations, in vivo tendon modulus, and MRI indicators of tendon ECM organization. We expect this work to show that AGEs via RAGE signaling are a principal mechanism driving changes in tendon ECM and subsequent reduction in biomechanical function in patients with diabetes. Defining the role of serum AGEs and RAGE signaling in the development of the diabetic tendon phenotype will provide an avenue to evaluate novel treatment approaches to reduce the impact of tendon complications in patients with diabetes. Our proposal fits NIAMS's mission of developing treatment strategies for tendon-related injuries. Our project addresses NIDDK’s mission of developing strategies to prevent and treat complications of diabetes.