Collagen Crosslinking Effects on Bone Fragility

描述（由申请人提供）：与年龄相关的非创伤性骨折是一个主要的公共卫生问题。尽管较低的骨量是与年龄相关的骨折发生率增加最常见的关联变量，但研究表明，骨材料抗骨折的抵抗力（韧性）随着年龄的增长而减弱。然而，与年龄相关的韧性丧失的机制尚不清楚。骨折过程中胶原变形和微裂纹形成是骨增韧的主要机制，初步研究表明，非酶（NEG）介导的骨胶原交联积累使有机网络变硬，减少骨中的胶原变形和微裂纹。因此，NEG介导的有机基体的硬化可能导致与年龄相关的韧性损失。此外，由于松质骨的屈服后和损伤行为与骨体积分数无关，与皮质骨相似，因此有机基质介导的增韧机制丧失可能对皮质骨和松质骨都是共同的。本研究的总体目标是研究neg介导的胶原交联对年龄相关的皮质和松质骨脆性增加的影响。该项目将使用体外核糖化、机械测试和对正常、糖基化、矿化和脱矿化的人类皮质骨和松质骨的微损伤评估来确定：（H1）骨胶原中NEG产物的年龄相关积累是否与有机基质刚度增加、增韧机制强度降低和裂纹扩展阻力降低有关；（H2）体外核糖基化对人体骨骼的胶原交联、有机基质刚度、增韧机制和抗裂纹扩展能力的影响与体内相似；（H3）与年龄相关的NEG含量、屈服后性能、有机基质刚度和增韧机制在皮质骨和松质骨中是相似的。该项目将：(a)通过提供neg介导的胶原交联作为骨质量的新指标，改善骨折风险的预测；(b)为改善骨质量的药物技术提供基础；(c)提高对糖尿病患者骨折的认识。

DESCRIPTION (provided by applicant): Age-related non-traumatic fractures are a major public health problem. Even though lower bone mass is the most commonly implicated variable for the age-related increase in fracture incidence, studies show that the resistance of bone material against fracture (toughness) diminishes with age. The mechanisms for the age related loss of toughness are, however, unknown. Collagen deformation and microcrack formation during fracture are the primary mechanisms of toughening in bone and preliminary studies demonstrate that nonenzymatically (NEG) mediated accumulation of crosslinks in bone collagen stiffen the organic network and reduced collagen deformation and microcracking in bone. The NEG mediated stiffening of the organic matrix may, therefore, cause the age-related loss of toughness. Furthermore, as post-yield and damage behaviors of cancellous bone are independent of the bone volume fraction and similar to that of cortical bone, the organic matrix mediated loss of toughening mechanisms may be common to both cortical and cancellous bones. The overall goal of this study is to investigate the effects of NEG-mediated collagen crosslinks on the age-related increase in cortical and cancellous bone fragility. The project will use in vitro ribosylation, mechanical testing and microdamage assessment of normal and glycated as well mineralized and demineralized human cortical and cancellous bones to determine whether: (H1) Age related accumulation of NEG products in bone collagen is associated with an increased organic matrix stiffness, reduced magnitude of toughening mechanisms and decreased crack propagation resistance; (H2) In vitro ribosylation causes similar modifications in the collagen crosslinks, organic matrix stiffness, toughening mechanisms and crack propagation resistance of human bone as are observed in vivo; and (H3) Age-related changes in the NEG content, post-yield properties, organic matrix stiffness and toughening mechanisms are similar for both cortical and cancellous bones. This project will: (a) improve the prediction of fracture risk by providing NEG-mediated collagen crosslinks as a new measure of bone quality; (b) provide a basis for a pharmaceutical technique to improve bone quality; (c) improve the understanding of fractures in diabetics.