Advanced Glycation End Products Effects on Bone Biomechanics

描述（由申请人提供）：将在小鼠模型中研究晚期糖基化终产物（AGE’s）对皮质骨生物力学特性的影响。众所周知，AGE形成的交联会损害骨骼的生物力学特性。AGE随着年龄的增长而积累，在某些疾病中也有发现，包括1型和2型糖尿病。该项目将采用独特的工具组合：生物力学测量、拉曼光谱和固态魔角旋转核磁共振光谱（MAS NMR），这些工具将提供骨矿物晶体结构和胶原蛋白二级结构中材料特性变化的详细信息。一个定制设计的转子，包括提供施加压缩载荷将用于弹性变形MAS核磁共振实验。外载荷将用于研究屈服点以外材料性能的化学结构。我们假设矿物的变化将包括矿物压缩和基质胶原链的扭曲，因为交联被扭曲，这些变化可以随着骨的核磁共振和拉曼光谱的变化而变化。核糖孵育将用于在小鼠皮质骨中产生AGE非酶交联。孵育时间的变化将用于改变交联丰度，并将为进一步研究提供背景信息。有了这些背景资料，我们将对年龄依赖性进行研究。我们假设矿物压缩和胶原蛋白扭曲会随着年龄的增长而增加。接下来，我们将研究AGE对NOD皮质骨（1型糖尿病小鼠模型）的影响。我们希望看到与衰老研究中类似的变化，但它们将在更早的年龄开始。我们还将开发AGE水平与全骨特性之间的相关性，以及核磁共振生成的超微结构水平组成数据与全骨特性之间的相关性，为超微结构变化如何转化为全骨功能并作为骨骼脆弱性的预测因子提供重要见解。最后，我们将开发MAS NMR提供的详细结构信息与拉曼光谱提供的不太详细的信息之间的相关性。这些相关性将用于增加从其他拉曼光谱研究中获得的信息，特别是对骨骼疾病的非侵入性诊断。

DESCRIPTION (provided by applicant): The effect of advanced glycation end products (AGE's) on the biomechanical properties of cortical bone will be studied in murine models. It is known that AGE's form cross-links that compromise bone biomechanical properties. AGE's accumlate with age and are also found in certain disorders, including type 1 and type 2- diabetes. The project will employ a unique combination of tools: biomechanical measurements, Raman spectroscopy and solid state magic angle spinning nuclear magnetic resonance spectroscopy (MAS NMR) that will provide detailed information on material property changes in the crystal structure of bone mineral crystallites and in the collagen secondary structure as the bone is mechanically loaded. A custom-designed rotor that includes provision for applying compressive load will be used for elastic deformation MAS NMR experiments. External loading will be used to study chemical structure correlates of material properties beyond the yield point. We hypothesize that changes in the mineral will include mineral compression and distortion of the matrix collagen chain as cross-links are distorted and that these changes can be followed as changes in both NMR and Raman spectra of the bone. Ribose incubation will be used to generate AGE non-enzymatic cross-links in murine cortical bone. Variations in incubation time will be used to vary the cross-link abundance and will provide background information for further studies. With this background information, a study of age- dependence will be undertaken. We hypothesize that mineral compression and collagen distortion will increase with age. Next, we will study the AGE effects in NOD cortical bone, a mouse model for type 1 diabetes. We expect to see changes similar to those in the aging study, but that they will begin at earlier ages. We will also develop correlations between AGE levels and whole bone properties and between ultrastructural level composition data generated by NMR and whole bone properties, providing important insights into how ultrastructural changes translate into whole bone function and serve as predictors of skeletal fragility. Finally, we will develop correlations between the detailed structural information provided by MAS NMR and the less detailed information provided by Raman spectroscopy. These correlations will be used to increase the information gained from other Raman spectroscopic studies, especially non-invasive diagnostics for bone disorders.