Collagen Crosslinking Effects on Bone Fragility

胶原交联对骨脆性的影响

• 批准号: 7116503
• 负责人: Deepak Vashishth
• 金额: $ 19.68万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116503
• 关键词: aging; biomechanics; collagen; crosslink; human tissue; normal ossification; tibia

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.

描述（由申请人提供）：脊柱相关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的最常见变量，但研究表明骨材料对骨折的抵抗力（韧性）随着年龄的增长而降低。然而，与年龄相关的韧性损失的机制是未知的。骨折过程中的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）介导的骨胶原中交联的积累破坏了有机网络，减少了骨中的胶原变形和微裂纹。因此，NEG介导的有机基质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，并且与皮质骨相似，因此有机基质介导的增韧机制丧失可能是皮质骨和松质骨共同的。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骨和松质骨脆性增加的影响。该项目将使用正常和糖化以及矿化和脱矿的人皮质骨和松质骨的体外核糖基化、机械测试和微损伤评估，以确定：（H1）骨胶原中NEG产物的年龄相关积累与有机基质刚度增加、增韧机制幅度降低和裂纹扩展阻力降低有关;（H2）体外核糖基化引起与体内观察到的人骨的胶原交联、有机基质刚度、增韧机制和抗裂纹扩展性类似的改变;和（H3）NEG含量，屈服后性质，对于皮质骨和松质骨，有机基质硬度和增韧机制是相似的。该项目将：（a）通过提供NG介导的胶原交联作为骨质量的新量度来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）改善对糖尿病患者骨折的理解。