Collagen Crosslinking Effects on Bone Fragility

胶原交联对骨脆性的影响

• 批准号: 7264503
• 负责人: Deepak Vashishth
• 金额: $ 22.53万
• 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/7264503
• 关键词: Affect; Age; Area; Behavior; Biochemical; Bone Matrix; Collagen; Data; Etiology; Fracture; Goals; Human; In Vitro; Incidence; Incidence Study; Incubated; Measures; Mechanics; Mediating; Modification; Nature; Numbers; Pharmacologic Substance; Procedures; Property; Public Health; Rate; Research Personnel; Residual state; Resistance; Ribose; Risk; Solutions; Specimen; Techniques; Testing; age related; base; bone; bone quality; bone strength; bone toughness; concept; crosslink; density; diabetic; improved; in vivo; programs; 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)：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的最常见的相关变量，但研究表明，骨材料对骨折的抵抗力(韧性)随着年龄的增长而减少。然而，与年龄相关的韧性丧失的机制尚不清楚。骨折过程中胶原的变形和微裂纹的形成是骨骼增韧的主要机制，初步研究表明，非酶(NEG)介导的交联物在骨胶原中的积累使有机网络变硬，减少了骨中的胶原变形和微裂纹。因此，NEG介导的有机基质的硬化可能导致与年龄相关的韧性损失。此外，由于松质骨的屈服和损伤后行为与骨体积分数无关，与皮质骨相似，有机基质介导的增韧机制的丧失可能在皮质骨和松质骨中是共同的。这项研究的总体目标是调查NEG介导的胶原交联物对与年龄相关的皮质骨和松质骨脆性增加的影响。该项目将使用正常的和糖化的以及矿化和脱矿的人类皮质骨和松质骨的体外核糖化、力学测试和微损伤评估来确定：(H1)与年龄相关的NEG产物在骨胶原中的积累是否与增加有机基质硬度、降低增韧机制的幅度和降低裂纹扩展阻力有关；(H2)体外核糖化导致人骨的胶原交联物、有机基质硬度、增韧机制和抗裂纹扩展能力与体内观察到的相似；以及(H3)皮质和松质骨的NEG含量、屈服后特性、有机基质硬度和增韧机制与年龄相关的变化相似。该项目将：(A)通过提供NEG介导的胶原交联物作为骨质量的新衡量标准，提高骨折风险的预测；(B)为提高骨质量的制药技术提供基础；(C)提高对糖尿病患者骨折的认识。