Determining the Biological Mechanisms of Pathological Cortical Porosity

摘要 皮质骨孔率是骨强度的主要决定因素。事实上，与年龄相关的皮质孔隙率增加 占随之而来的皮质骨强度降低的75%以上。此外，我们集团和 其他研究人员发现，皮质孔隙度的增加与患者骨折患病率的升高有关。 患有2型糖尿病(T2D)。尽管皮质孔隙率在生物力学上具有重要意义，但 皮质孔扩张是未知的。填补这一知识空白将阐明适当的细胞靶点 药物开发，以防止或逆转病理性毛孔发育和相关的骨骼脆性。 影响毛孔扩张的生物系统可以通过可视化皮质毛孔的含量来揭示。 太空。我们的团队开发了基于磁共振成像(MRI)的创新采集和 用于可视化皮质毛孔内的血管和脂肪的处理技术，这两种技术都已经 与毛孔扩张有关。我们建议检测在纵向的过程中形成的新的孔隙空间 骨骼成像研究，确定新的孔隙空间的含量，并通过这种方式确定生物 系统(S)驱动新的孔隙空间的发展。拟议的家长研究是一项正在进行的纵向研究 T2D背景下皮质毛孔发育的研究。家长研究的目的是量化纵向 T2D患者和健康对照组皮质孔隙度的变化。此外，家长研究还应用了我们的 基于MRI的孔隙含量可视化技术以基线时间点为研究对象(仅限)比较孔隙 T2D和健康队列之间的含量，并评估毛孔含量与临床的相关性 血管健康和脂肪代谢的评估。父母研究不包括随访时的磁共振成像， 因此无法回答这个问题：在T2D和健康对照组中，是血管系统， 骨髓脂肪，还是两者都导致了随着时间的推移皮质孔隙率增加？在这项附属研究中，我们会加入 以MRI为基础的孔洞含量可视化对家长的随访研究。我们将直接将 在2年的随访期内发展和/或扩大的毛孔的含量，并以这种方式揭示 与孔隙空间扩张相关的机制。通过利用父母的研究，我们捕获了一口井- 特征队列，已获得所有必要的临床和影像数据，但 复查核磁共振。此申请符合拨款公告的时间敏感性要求：为了 有效地利用已建立的亲代研究队列，孔隙含量可视化技术必须 到2020年初增加。这项工作将确定驱动孔隙度增加的生物系统与 衰老和T2D，以及预防或逆转与年龄和T2D相关的潜在药物靶点 病理性多孔性和骨脆性，为未来的治疗研究奠定了基础。和将军在一起 随着人口老龄化和T2D患病率的上升，这项研究有可能产生巨大的临床影响。

SUMMARY Cortical bone porosity is a major determinant of bone strength. In fact, age-related increases in cortical porosity account for more than 75% of the concomitant reduction in cortical bone strength. Further, our group and others have found that increased cortical porosity is associated with elevated fracture prevalence in patients with type 2 diabetes (T2D). Despite the biomechanical importance of cortical porosity, the biological drivers of cortical pore expansion are unknown. Filling this knowledge gap will elucidate appropriate cellular targets for drug development to prevent or reverse pathological pore development and the associated skeletal fragility. The biological systems influencing pore expansion can be revealed by visualizing the content of cortical pore space. Our team has developed innovative magnetic resonance imaging (MRI)-based acquisition and processing techniques to visualize vasculature and fat within cortical pores, both of which have been implicated in pore expansion. We propose to detect new pore space formed over the course of a longitudinal skeletal imaging study, identify the content of that new pore space, and in this way determine the biological system(s) driving development of the new pore space. The proposed parent study is an ongoing longitudinal study of cortical pore development in the context of T2D. The aim of the parent study is to quantify longitudinal changes in cortical porosity in patients with T2D and in healthy controls. Further, the parent study applies our MRI-based pore content visualization technique to the baseline time-point of the study (only) to compare pore content between T2D and healthy cohorts and to evaluate associations between pore content and clinical evaluations of vascular health and fat metabolism. The parent study does not include MRI at the follow-up visit, and therefore will not be able to answer the question: In T2D and healthy controls, is the vascular system, the marrow fat, or both responsible for increased cortical porosity over time? In this ancillary study, we will add the MRI-based pore content visualization to the follow-up visit of the parent study. We will directly image the content of pores that develop and/or expand over the 2-year follow-up period, and in this way reveal the mechanisms associated with pore space expansion. By leveraging the parent study we capture a well- characterized cohort, with all necessary clinical and imaging data already acquired, with the exception of the follow-up MRI. This application meets the time sensitivity requirement of the funding announcement: in order to efficiently leverage the established parent study cohort, the pore content visualization technique must be added by early 2020. This work will identify the biological systems driving increased porosity associated with aging and T2D, as well as potential drug targets for the prevention or reversal of age- and T2D-related pathological porosity and bone fragility, laying the groundwork for future therapeutic studies. With the general populating aging and the prevalence of T2D rising, this study has the potential for immense clinical impact.