Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices

Ural, Anı; Janeiro, Colleen; Karim, Lamya; Diab, Tamim; Vashishth, Deepak

doi:10.1007/s00198-014-2938-4

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…fAGEs were indeed increased by ~81% in ribose‐treated specimens compared with vehicles. The AGE levels in vehicles were like those reported in human cortical bone in vivo in two studies but were higher than those reported by another study (Table ). It is difficult to ascertain why the third study reports much lower AGE values as that study also used human female tibias from a similar age range.…”

Section: Discussionsupporting

confidence: 66%

“…Moreover, studies using diabetic animals suggest that increased AGEs are associated with lower bone stiffness and are more susceptible to microcrack propagation compared with non‐diabetic controls, but there is little information regarding crack initiation and propagation due to AGEs in human bone . Further, about 12 studies in human bone focused on studying the effect of non‐enzymatic glycation on cancellous bone mechanical behavior, but only six studies report findings on cortical bone, two of which utilize bovine bone . There is some indication that in diabetes (where AGEs are particularly relevant) cortical bone is the primary bone type affected with a reduced quality .…”

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confidence: 99%

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In Vitro‐Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Merlo

Aaronson

Vaidya

et al. 2019

Journal Orthopaedic Research

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Advanced glycation end-products (AGEs) have been suggested to contribute to bone fragility in type 2 diabetes (T2D). AGEs can be induced through in vitro sugar incubations but there is limited data on the effect of total fluorescent AGEs on mechanical properties of human cortical bone, which may have altered characteristics in T2D. Thus, to examine the effect of AGEs on bone directly in T2D patients with uncontrolled sugar levels, it is essential to first understand the fundamental mechanisms by studying the effects of controlled in vitro-induced AGEs on cortical bone mechanical behavior. Here, human cortical bone specimens from female cadaveric tibias (ages 57-87) were incubated in an in vitro 0.6 M ribose or vehicle solution (n = 20/group) for 10 days at 37°C, their mechanical properties were assessed by microindentation and fracture toughness tests, and induced AGE levels were quantified through a fluorometric assay. Results indicated that ribose-incubated bone had significantly more AGEs (+81%, p ≤ 0.005), lower elastic modulus assessed by traditional microindentation, and lower fracture toughness compared with vehicle controls. Furthermore, based on pooled data, increased AGEs were significantly correlated with deteriorated mechanical properties. The findings presented here show that the accumulation of AGEs allows for lower stiffness and increased ability to initiate a crack in human cortical bone. Statement of clinical significance: High sugar levels as in T2D results in deteriorated bone quality via AGE accumulation with a consequent weakening in bone's mechanical integrity.

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Section: Discussionsupporting

confidence: 66%

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confidence: 99%

In Vitro‐Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Merlo

Aaronson

Vaidya

et al. 2019

Journal Orthopaedic Research

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“…Therefore, the negative spatial correlation between resorption cavities and microdamage in the current study may be a result of more ductile tissue near trabecular surfaces (due to younger local tissue age). However, increased non-enzymatic glycation (a trait associated with increased tissue brittleness [32]) has been shown to impair osteoclastic bone resorption in vitro [40] and is negatively correlated with resorption cavities in cortical bone [41]. If such a negative correlation also exists in cancellous bone it could also explain the negative correlation between microdamage and resorption cavities we observed.…”

Section: 0 Discussionmentioning

confidence: 91%

Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces

Goff

Lambers

Nguyen

et al. 2015

Bone

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Impaired bone toughness is increasingly recognized as a contributor to fragility fractures. At the tissue level, toughness is related to the ability of bone tissue to resist the development of microscopic cracks or other tissue damage. While most of our understanding of microdamage is derived from studies of cortical bone, the majority of fragility fractures occur in regions of the skeleton dominated by cancellous bone. The development of tissue microdamage in cancellous bone may differ from that in cortical bone due to differences in microstructure and tissue ultrastructure. To gain insight into how microdamage accumulates in cancellous bone we determined the changes in number, size and location of microdamage sites following different amounts of cyclic compressive loading. Human vertebral cancellous bone specimens (n=32, 10 male donors, 6 female donors, age 76 ± 8.8, mean ± SD) were subjected to sub-failure cyclic compressive loading and microdamage was evaluated in three-dimensions. Only a few large microdamage sites (the largest 10%) accounted for 70% of all microdamage caused by cyclic loading. The number of large microdamage sites was a better predictor of reductions in Young’s modulus caused by cyclic loading than overall damage volume fraction (DV/BV). The majority of microdamage volume (69.12 ± 7.04%) was located more than 30 μm (the average erosion depth) from trabecular surfaces, suggesting that microdamage occurs primarily within interstitial regions of cancellous bone. Additionally, microdamage was less likely to be near resorption cavities than other bone surfaces (p<0.05), challenging the idea that stress risers caused by resorption cavities influence fatigue failure of cancellous bone. Together, these findings suggest that reductions in apparent level mechanical performance during fatigue loading are the result of only a few large microdamage sites and that microdamage accumulation in fatigue is likely dominated by heterogeneity in tissue material properties rather than stress concentrations caused by micro-scale geometry.

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“…AGEs have been implicated in the deterioration of tissue properties in many different tissues, including bone. [11] AGE crosslinking in collagen has been demonstrated to increase bone fragility [12; 13; 14; 15; 16; 17]. …”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of glycation adducts on osteocalcin

Thomas

Cleland

Zhang

et al. 2017

Analytical Biochemistry

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Osteocalcin is an important extracellular matrix bone protein that contributes to the structural properties of bone through its interactions with hydroxyapatite mineral and with collagen I. This role may be affected by glycation, a labile modification the levels of which has been shown to correlate with bone fragility. Glycation starts with the spontaneous addition of a sugar onto a free amine group on a protein, forming an Amadori product, and then proceeds through several environment-dependent stages resulting in the formation of an advanced glycation end product. Here, we induce the first step of this modification on synthetic osteocalcin, and then use multiple mass spectrometry fragmentation techniques to determine the location of this modification. Collision-induced dissociation resulted in spectra dominated by neutral loss, and was unable to identify Amadori products. Electron-transfer dissociation showed that the Amadori product formed solely on osteocalcin’s N-terminus. This suggests that the glycation of osteocalcin is unlikely to interfere with osteocalcin’s interaction with hydroxyapatite. Instead, glycation may interfere with its interaction with collagen I or another bone protein, osteopontin. Potentially, the levels of glycated osteocalcin fragments released from bone during bone resorption could be used to assess bone quality, should the N-terminal fragments be targeted.

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Association between non-enzymatic glycation, resorption, and microdamage in human tibial cortices

Cited by 24 publications

References 46 publications

In Vitro‐Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

In Vitro‐Induced High Sugar Environments Deteriorate Human Cortical Bone Elastic Modulus and Fracture Toughness

Fatigue-induced microdamage in cancellous bone occurs distant from resorption cavities and trabecular surfaces

Identification and characterization of glycation adducts on osteocalcin

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