Bone Robustness as a Biomarker of Skeletal Aging and Fragility

骨骼坚固性作为骨骼衰老和脆弱性的生物标志物

• 批准号: 9069414
• 负责人: KARL J JEPSEN
• 金额: $ 41.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069414
• 关键词: Accounting; Address; Adult; Affect; Age-Related Bone Loss; Aging; Aging-Related Process; Apoptosis; Area; Biological; Biological Markers; Biology of Aging; Biomechanics; Bone remodeling; Clinical; Collagen; Complex; Deterioration; Diagnosis; Ethnic Origin; Experimental Models; Fracture; Future; Goals; Growth; Health; Homeostasis; Human; Incidence; Individual; Individual Differences; Investigation; Knowledge; Lead; Left; Length; Life; Measures; Mechanics; Military Personnel; Minerals; Musculoskeletal; Nature; Osteon; Persons; Phenotype; Physiological; Porosity; Process; Property; Recruitment Activity; Reporting; Research; Resistance; Risk; Sampling; Signal Transduction; Site; Skeletal system; Stress Fractures; Structure; System; Technology; Testing; Time; Tissues; Variant; Work; age related; base; bone; bone loss; bone mass; bone strength; crosslink; density; functional adaptation; insight; sex; skeletal; tibia; trait

DESCRIPTION (provided by applicant): Reducing age-related fragility fractures remains a major objective of musculoskeletal research. Currently, increased fracture risk is diagnosed after an individual loses bone mass and strength. This strategy is not optimal as a long-term fracture reduction strategy because it leads to a transient loss in strength that unnecessarily increases fracture risk prior to treatment. An ideal fracture-reduction strategy would aim to maintain bone strength over time rather than attempt to replace bone after significant loss. However, we lack crucial information about inter-individual differences in skeletal aging that limits existing technologies from accurately predicting a person's future bone strength prior to age-related bone loss. Our research examining the complex adaptive nature of bone identified a common morphological trait, robustness, that may serve as a new biomarker for predicting fracture risk earlier in life and for providing insight into fragility-related biological activitie. Robustness (a measure of transverse size relative to length) is established early postnatally and varies widely among individuals. Our key finding was that the natural variation in robustness was accompanied by highly coordinated changes in cortical area and tissue mineral density. Our work in human bone established these functional interactions in the context of whole bone stiffness (mechanical homeostasis), and the traits examined were largely limited to those that could be measured non-invasively. The extent to which other matrix variables (e.g., collagen crosslinking) are coordinately adjusted to accommodate the natural variation in robustness, how the functional interactions among these extended traits affect fracture resistance properties (e.g., strength, ductility, toughness, fatigability), and how these relationships change with aging remain unclear. To address these questions, we propose to study bone as a complex adaptive system using the natural variation in robustness as an experimental model to predict inter-individual differences in BMU-based remodeling (Aim 1), fracture resistance (Aim 2), and skeletal aging (Aim 3). Successful completion of these Aims will provide fundamental new knowledge about the functional adaptation process in bone, and will establish the complex adaptive nature of the skeletal system as a biomechanical mechanism contributing to differential aging and fracture resistance among individuals. Our long term goal is to use this knowledge to develop preventative personalized technologies aimed at maintaining bone strength with aging to reduce fracture incidence.

描述(由申请人提供)：减少与年龄相关的脆性骨折仍然是肌肉骨骼研究的主要目标。目前，骨折风险增加是在个体失去骨量和强度后被诊断出来的。作为一种长期的骨折整复策略，这一策略并不是最优的，因为它会导致一过性的力量丧失，从而在治疗前不必要地增加骨折风险。理想的骨折整复策略应该着眼于随着时间的推移保持骨骼强度，而不是在严重丧失后试图更换骨骼。然而，我们缺乏关于骨骼老化的个体间差异的关键信息，这种差异限制了现有技术在与年龄相关的骨丢失之前准确预测一个人的未来骨强度。我们对骨骼复杂适应性的研究发现了一种共同的形态特征，即健壮性，这可能成为一种新的生物标记物，用于预测早期骨折的风险，并为了解与脆性相关的生物活动提供洞察。健壮性(相对于长度的横向大小的测量)是在出生后早期建立的，个体之间差异很大。我们的关键发现是，健壮性的自然变化伴随着皮质面积和组织矿物质密度的高度协调变化。我们在人骨中的工作建立了在整个骨骼硬度(机械稳态)的背景下的这些功能相互作用，所检查的特征主要限于那些可以非侵入性测量的特征。协调调整其他基质变量(例如，胶原交联度)以适应健壮性的自然变化的程度，这些扩展特征之间的功能相互作用如何影响抗断裂性能(例如，强度、延展性、韧性、疲劳性)，以及这些关系如何随年龄变化 目前仍不清楚。为了解决这些问题，我们建议将骨骼作为一个复杂的适应系统来研究，使用健壮性的自然变化作为实验模型，以预测基于BMU的重塑(目标1)、抗折性(目标2)和骨骼老化(目标3)的个体间差异。这些目标的成功完成将为了解骨骼的功能适应过程提供基本的新知识，并将确立骨骼系统作为生物力学机制的复杂适应性，有助于个体之间的不同衰老和骨折抵抗。我们的长期目标是利用这些知识开发预防性个性化技术，旨在随着年龄的增长保持骨骼强度，以减少骨折发生率。