Diabetes-Related Changes Affecting Bone Quality

影响骨质量的糖尿病相关变化

• 批准号: 10683072
• 负责人: Jeffry Stephen Nyman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683072
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Amides; Architecture; Binding; Biomechanics; Bone Density; Bone Matrix; Bone structure; Cadaver; Characteristics; Clinical; Clinical assessments; Collagen; Defect; Diabetes Mellitus; Diagnosis; Diagnostic Procedure; Discipline; Dual-Energy X-Ray Absorptiometry; Electrons; Event; FDA approved; Fatigue; Female; Femur; Foundations; Fracture; Gender; Glycosylated hemoglobin A; Goals; Hip Fractures; Hip region structure; Hydrogen Bonding; Hydroxylation; Image; Individual; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measurement; Measures; Modification; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Osteoporosis; Pathogenicity; Patient risk; Patients; Periodicity; Pharmaceutical Preparations; Post-Translational Protein Processing; Prevalence; Prevention; Property; Proteins; Protons; Quality of life; Raman Spectrum Analysis; Research; Research Personnel; Resistance; Resolution; Risk; Sampling; Signal Transduction; Structure; Techniques; Technology; Time; Tissues; Veterans; Water; Woman; bone; bone quality; bone toughness; carboxylate; carboxylation; clinical diagnosis; clinical diagnostics; cortical bone; density; diabetic; diabetic bone disease; diagnostic tool; fracture risk; glycosylation; improved; indexing; male; mechanical properties; men; microCT; mineralization; minimally invasive; mortality; non-diabetic; novel; novel diagnostics; novel strategies; recruit; risk prediction; sex; therapeutic target; tibia; tool

Project Summary/Abstract: The risk of bone fracture and subsequent high morbidity increases with the progression of type 2 diabetes (T2D), and the clinical assessment of bone mineral density (BMD) is not particularly effective in diagnosing this risk. Moreover, lowering fracture risk among patients with T2D requires an understanding of the changes in the bone that affect fracture resistance. Addressing these unmet needs, the proposed project aims i) to determine the primary biomechanical reason for the increase in fracture risk with T2D, ii) to identify molecular changes in the bone matrix that can significantly affect fracture resistance, and iii) to ascertain the ability of matrix-sensitive tools to assess significant differences in bone quality between age-matched non-diabetics and diabetic individuals. In Aim 1, cadaveric bone from non-diabetic and T2D donors matching for age and gender will be comprehensively analyzed to determine whether the primary T2D-related decrease in fracture resistance is lower bone toughness, lower fatigue resistance, and/or lower fracture toughness as opposed to lower strength at the whole-bone- and material-level. Moreover, the ability of matrix characteristics to explain T2D-related differences in these mechanical properties of bone will be assessed in relation to volumetric BMD and micro-structure (assessed by micro-computed tomography) as well as the degree of mineralization and osteonal density (assessed backscattered electron imaging). Matrix characteristics will include secondary structure of collagen I as determined by sub-peak ratios of the Amide I band from Raman spectroscopy (RS), bound and pore water volume fractions as determined by proton nuclear magnetic resonance (NMR) relaxometry, and resistance to microindentation properties as determined by both cyclic and impact reference point (RPI). In Aim 2, the focus will be on the contribution of novel molecular mechanisms to the underlying diabetic changes in matrix-bound water and collagen structure. Specifically, emphasis will be placed on post-translational modifications (PTMs) of collagen I and non-collagenous bone matrix proteins as a mechanism that affects hydrogen bonding between water and the matrix. Implicated in diabetes, these PTMs will include non-enzymatic advanced glycation end products (AGEs) as well as enzymatic hydroxylation, glycosylation, and carboxylation. In Aim 3, matrix-sensitive, clinical techniques will determine whether bone quality is significantly different between patients without diabetes and patients with established T2D. By matching age and BMD-derived T-scores between the groups, we will ascertain whether bone material strength index from impact RPI, bound and pore water concentrations from ultra-short time-to-echo magnetic resonance imaging (UTE-MRI) of NMR signals (T2), and Amide I sub-peak ratios from spatially offset, transcutaneous RS, all acquired at the tibia mid-shaft, will potentially add value to the clinical assessment of fracture risk. The completion of the Aims of this proposal will lay the foundation for use of matrix-sensitive tools in clinical diagnostics of diabetic bone disease and potentially identify specific targets within the bone matrix for lowering fracture risk among diabetics.

项目概要/摘要： 随着2型糖尿病（T2 D）的进展，骨折和随后的高发病率的风险增加， 并且骨矿物质密度（BMD）的临床评估在诊断这种风险方面不是特别有效。 此外，降低T2 D患者的骨折风险需要了解骨骼的变化 影响抗断裂性。针对这些未满足的需求，拟议项目的目标是：i）确定 T2 D骨折风险增加的主要生物力学原因，ii）识别T2 D中的分子变化， 可以显著影响抗骨折性的骨基质，和iii）确定基质敏感工具的能力 评估年龄匹配的非糖尿病患者和糖尿病患者之间骨质量的显著差异。在 目的1，将来自年龄和性别匹配的非糖尿病和T2 D供体的尸体骨全面地 分析以确定主要的T2 D相关的抗断裂性降低是否是较低的骨韧性， 较低的抗疲劳性和/或较低的断裂韧性，与全骨的较低强度相反， 材料级。此外，基质特征解释T2 D相关差异的能力， 将根据体积骨密度和微观结构评估骨骼的机械性能（由 微计算机断层扫描）以及矿化程度和骨密度（评估 背散射电子成像）。基质特征将包括胶原蛋白I的二级结构， 通过来自拉曼光谱（RS）的酰胺I带的亚峰比、结合水和孔隙水测定 通过质子核磁共振（NMR）弛豫测定法测定的体积分数，以及对 通过循环和冲击参考点（RPI）确定的微压痕性能。在目标2中， 将是新的分子机制的基础糖尿病的变化，在基质结合的贡献， 水和胶原蛋白结构。具体而言，重点将放在翻译后修饰（PTM）的 胶原蛋白I和非胶原骨基质蛋白作为影响氢键之间的机制 水和矩阵。与糖尿病有关，这些PTM将包括非酶促晚期糖基化终末产物。 糖基化和羧化。在目标3中，基质敏感， 临床技术将确定非糖尿病患者的骨质量是否有显著差异 和已确诊的T2 D患者。通过匹配各组之间的年龄和BMD衍生的T分数，我们将 确定骨材料强度指数是否影响RPI，结合水和孔隙水浓度是否影响RPI， NMR信号（T2）的超短时间回波磁共振成像（UTE-MRI），以及酰胺I亚峰 所有在胫骨中段采集的空间偏移、经皮RS的比值将潜在地增加 骨折风险的临床评估。本提案目标的完成将为使用 基质敏感性工具在糖尿病骨疾病的临床诊断中的应用，并可能识别 降低糖尿病患者骨折风险的骨基质。

项目成果

Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone.

• DOI: 10.1016/j.bone.2020.115254
• 发表时间: 2020-01
• 期刊: Bone
• 影响因子: 4.1
• 作者: K. Thrailkill;R. C. Bunn;S. Uppuganti;Philip D. Ray;Kate Garrett;I. Popescu;J. Pennings;J. Fowlkes;J. Nyman

Sensitivity of the amide I band to matrix manipulation in bone: a Raman micro-spectroscopy and spatially offset Raman spectroscopy study.

酰胺 I 带对骨基质操作的敏感性：拉曼显微光谱和空间偏移拉曼光谱研究。

• DOI: 10.1039/d3an00527e
• 发表时间: 2023
• 期刊: The Analyst
• 作者: Ahmed,Rafay;Unal,Mustafa;Gautam,Rekha;Uppuganti,Sasidhar;Derasari,Shrey;Mahadevan-Jansen,Anita;Nyman,JeffryS
• 通讯作者: Nyman,JeffryS

Canagliflozin, an SGLT2 inhibitor, corrects glycemic dysregulation in TallyHO model of T2D but only partially prevents bone deficits.

• DOI: 10.1016/j.bone.2020.115625
• 发表时间: 2020-12
• 期刊: Bone
• 影响因子: 4.1
• 作者: Thrailkill KM;Bunn RC;Uppuganti S;Ray P;Popescu I;Kalaitzoglou E;Fowlkes JL;Nyman JS
• 通讯作者: Nyman JS

Compositional assessment of bone by Raman spectroscopy.

• DOI: 10.1039/d1an01560e
• 发表时间: 2021-12-06
• 期刊: The Analyst
• 作者: Unal M;Ahmed R;Mahadevan-Jansen A;Nyman JS
• 通讯作者: Nyman JS