Reduced bone quality is a key determinant of skeletal fragility in CKD, but the details of thiseffect are not well defined. Non-enzymatic collagen crosslinks (formed via advanced glycationend-products, AGEs) negatively affect bone mechanical properties and AGEs are elevated inthe blood and bone of patients and animals with advanced CKD. We propose that skeletalaccumulation of AGE collagen cross links may play a critical role in CKD skeletal fragility andreducing AGEs may represent a novel approach to reduce fracture risk in CKD patients. Theoverall goal of this study is to test the hypothesis that skeletal AGEs induce negativemechanical and cellular effects in CKD and that circulating AGE levels can help in CKD patientfracture discrimination. This goal will be accomplished through a combination of pre-clinicalexperiments using our established model of progressive CKD (the Cy/+ rat), novel humanbiopsy assays, and state-of-the art bone imaging with second generation high resolutionperipheral quantitative computed tomography. The multi-university interdisciplinary team isperfectly positioned to undertake this translational work based on their clinical and preclinicalexpertise in bone, collagen/AGEs, mechanics, and CKD. In Aim 1 we will determine if AGE-lowering drug treatments that reduce endogenous AGE production or gastrointestinal absorptionimprove the skeletal properties of animals with progressive CKD. In Aim 2 we will assess theeffect of disease severity on human bone AGE accumulation and its relationship to mechanicalproperties by measuring bone AGE levels and mechanical properties from transiliac crest bonebiopsies from patients with CKD. In Aim 3, we will quantify the ability of AGE levels to improvefracture discrimination in CKD patients. In Aim 4, we will determine if AGE accumulation in thebone extracellular matrix impairs bone marrow derived osteoblast differentiation, function andAGE receptor expression. The current proposal will build on our body of work characterizingabnormal bone quality in patients with CKD by studying how agents that modulate AGEsthrough different mechanisms alter skeletal accumulation of AGEs and bone mechanicalproperties in animals and humans. If these studies show efficacy in benefiting skeletalmechanical properties, these treatments could be rapidly translated into the clinical setting.
|Effective start/end date||8/5/16 → 6/30/20|
- National Institutes of Health: $471,810.00