Collagen Crosslinking Effects on Bone Fragility

胶原交联对骨脆性的影响

• 批准号: 7653664
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653664
• 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; Pharmacologic Substance; Procedures; Property; Public Health; Research Personnel; Residual state; Resistance; Ribose; Risk; Solutions; Specimen; Techniques; Testing; age related; base; bone; bone age; bone mass; bone quality; bone strength; bone toughness; 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。尽管较低的骨骼质量是骨折发生率与年龄相关的增加最常见的变量，但研究表明，骨料对骨折（韧性）的抗性随着年龄的增长而减少。但是，与年龄相关的韧性损失的机制是未知的。骨折过程中胶原蛋白的变形和微裂纹形成是骨骼中变形的主要机制，初步研究表明，骨胶原蛋白中的非酶（负）介导的交联积累使有机网络加强并减少了骨骼中的胶原蛋白变形和骨骼中的微裂纹。因此，否定有机基质的僵硬可能会导致与年龄相关的韧性丧失。此外，由于取消骨的后产物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韧性损失可能是皮质和骨骼骨骼的共同点。这项研究的总体目的是研究负介导的胶原蛋白交联对与年龄相关的皮质和取消骨脆性增加的影响。该项目将使用体外核糖基化，机械测试以及对正常和糖化以及矿化和去矿化的人皮质和取消骨骼的微宏评估，以确定：（H1）与年龄相关的neg产物在骨胶原蛋白中相关的积累是否与有机矩阵刚度增加的幅度降低机械性能和降低的机械性能相关，并具有降低的机械性能和降低的电阻。 （H2）体外核糖基化在胶原蛋白交联，有机基质刚度，坚韧机制和人骨裂纹耐药性中引起类似的修饰。 （H3）与年龄相关的NEG含量，后产物的特性，有机基质刚度和韧性机制的变化对于皮质和取消骨骼都是相似的。该项目将：（a）通过提供否定介导的胶原蛋白交联作为骨质质量的新量度来改善断裂风险的预测； （b）为提高骨质质量的药物技术提供了基础； （c）提高对糖尿病患者骨折的理解。

项目成果

The relative contributions of non-enzymatic glycation and cortical porosity on the fracture toughness of aging bone.

• DOI: 10.1016/j.jbiomech.2010.10.016
• 发表时间: 2011-01-11
• 期刊: JOURNAL OF BIOMECHANICS
• 影响因子: 2.4
• 作者: Tang, S. Y.;Vashishth, D.
• 通讯作者: Vashishth, D.

Techniques for advanced glycation end product measurements for diabetic bone disease: pitfalls and future directions.

• DOI: 10.1097/med.0000000000000736
• 发表时间: 2022-08-01
• 期刊: CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY
• 影响因子: 3.2
• 作者: Sroga, Grazyna E.;Stephen, Samuel J.;Wang, Bowen;Vashishth, Deepak
• 通讯作者: Vashishth, Deepak

The effect of strain rate on fracture toughness of human cortical bone: a finite element study.

• DOI: 10.1016/j.jmbbm.2011.03.011
• 发表时间: 2011-10
• 期刊: JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS
• 影响因子: 3.9
• 作者: Ural, Ani;Zioupos, Peter;Buchanan, Drew;Vashishth, Deepak
• 通讯作者: Vashishth, Deepak

UPLC methodology for identification and quantitation of naturally fluorescent crosslinks in proteins: a study of bone collagen.

• DOI: 10.1016/j.jchromb.2010.12.024
• 发表时间: 2011-02-15
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Sroga, Grazyna E.;Vashishth, Deepak
• 通讯作者: Vashishth, Deepak

Advanced Glycation End-products and Bone Fractures.

高级糖化终产物和骨折。

• DOI: 10.1138/20090390
• 发表时间: 2009
• 期刊: IBMS boneKEy
• 作者: Vashishth,Deepak