Abstract
Fractures, particularly at the lower extremities and hip, are a complication of diabetes. In both type 1 (T1D) and type 2 diabetes (T2D), fracture risk is disproportionately worse than that predicted from the measurement of bone mineral density. Although an explanation for this discrepancy is the presence of organic matrix abnormalities, it has not been fully elucidated how advanced glycation endproducts (AGEs) relate to bone deterioration at both the macroscopic and microscopic levels. We hypothesized that there would be a relationship between skeletal AGE levels (determined by Raman microspectroscopy at specific anatomical locations) and bone macroscopic and microscopic properties, as demonstrated by the biomechanical measures of crack growth and microindentation respectively. We found that in OVE26 mice, a transgenic model of severe early onset T1D, AGEs were increased by Raman (carboxymethyl-lysine [CML] wildtype (WT): 0.0143 ±0.0005 vs T1D: 0.0175 ±0.0002, p = 0.003) at the periosteal surface. These differences were associated with less tough bone in T1D by fracture mechanics (propagation toughness WT: 4.73 ± 0.32 vs T1D: 3.39 ± 0.24 NM/m1/2, p = 0.010) and by reference point indentation (indentation distance increase WT: 6.85 ± 0.44 vs T1D: 9.04 ± 0.77 μm; p = 0.043). Within T1D, higher AGEs by Raman correlated inversely with macroscopic bone toughness. These data add to the existing body of knowledge regarding AGEs and the relationship between skeletal AGEs with biomechanical indices.
Highlights
Substantial evidence exists that in addition to the well-known complications of diabetes, such as neuropathy, nephropathy and retinopathy, increased fracture risk is an important morbidity [1]
advanced glycation endproducts (AGEs) are a diverse group of compounds that are generated through the non-enzymatic glycation or glycoxidation of proteins, lipids, and nucleic acids [4] with the best-studied being carboxymethyl-lysine (CML) and pentosidine [5,6,7,8]
In contrast to postmenopausal osteoporosis, where fracture risk is linked to bone mass, bone fragility in diabetes might stem, at least in part, from deficits in organic matrix composition
Summary
Substantial evidence exists that in addition to the well-known complications of diabetes, such as neuropathy, nephropathy and retinopathy, increased fracture risk is an important morbidity [1]. Fracture risk is not fully accounted for in either type 1 (T1D) or type 2 (T2D) diabetes by measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry [1]. An explanation for this discordance between fracture risk and BMD may lie in the diabetic. The accumulation of advanced glycation endproducts (AGEs) in Type I collagen is elevated [2, 3]. AGEs are markedly increased in patients with diabetes [7], forming non-enzymatic cross-links within and across collagen fibers [9]
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