A direct role of collagen glycation in bone fracture.
A direct role of collagen glycation in bone fracture.
复制标题
DOI：
10.1016/j.jmbbm.2015.08.012
复制
发表时间：
2015-12
影响因子：
3.9
通讯作者：
Vashishth D
中科院分区：
文献类型：
--
作者：
Poundarik AA;Wu PC;Evis Z;Sroga GE;Ural A;Rubin M;Vashishth D
非酶糖基化（NEG）是一种由糖尿病等疾病加速的与年龄相关的过程，并导致晚期糖基化终产物（AGEs）的积累。NG介导的骨有机基质（主要是I型胶原）的修饰与损害骨骼生理学和力学有关。在这里，我们提出的证据，从体外和体内模型，并建立了因果关系的胶原蛋白糖化和改变骨折在多个长度尺度。通过原子力光谱，我们确定NEG损害胶原蛋白耗散能量的能力。体外糖化人骨样本的力学测试显示，由于NEG导致的AGE积累显著降低了有机和矿化基质蠕变的能力，并导致骨在通常与跌倒相关的低水平应变（3000-5000 μ应变）下的冲击下断裂。对不同年龄的NEG改性人皮质骨及其年龄匹配对照的断裂力学测试显示，NEG破坏了基于微裂纹的增韧机制，并降低了所有年龄组的骨传播和起始断裂韧性。基于实验和建模数据开发了一个全面的机制模型，以解释NEG和AGEs如何与骨脆性相关并预测骨脆性。此外，对糖尿病小鼠骨的断裂力学和压痕测试显示，糖尿病介导的NEG严重破坏体内骨基质质量。最后，我们表明，AGEs是预测老年人骨质量和骨折风险的诊断应用。
Non-enzymatic glycation (NEG) is an age-related process accelerated by diseases like diabetes, and causes the accumulation of advanced glycation end-products (AGEs). NEG-mediated modification of bone’s organic matrix, principally collagen type-I, has been implicated in impairing skeletal physiology and mechanics. Here, we present evidence, from in vitro and in vivo models, and establish a causal relationship between collagen glycation and alterations in bone fracture at multiple length scales. Through atomic force spectroscopy, we established that NEG impairs collagen’s ability to dissipate energy. Mechanical testing of in vitro glycated human bone specimen revealed that AGE accumulation due to NEG dramatically reduces the capacity of organic and mineralized matrix to creep and caused bone to fracture under impact at low levels of strain (3000–5000 μstrain) typically associated with fall. Fracture mechanics tests of NEG modified human cortical bone of varying ages, and their age-matched controls revealed that NEG disrupted microcracking based toughening mechanisms and reduced bone propagation and initiation fracture toughness across all age groups. A comprehensive mechanistic model, based on experimental and modeling data, was developed to explain how NEG and AGEs are causal to, and predictive of bone fragility. Furthermore, fracture mechanics and indentation testing on diabetic mice bones revealed that diabetes mediated NEG severely disrupts bone matrix quality in vivo. Finally, we show that AGEs are predictive of bone quality in aging humans and have diagnostic applications in fracture risk.