Effects of Reduced Mechanical Loading on Bone Microarchitecture and Cell Function

减少机械负荷对骨微结构和细胞功能的影响

• 批准号: 1400247
• 负责人: Susannah Fritton
• 金额: $ 39万
• 依托单位: CUNY City College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1400247&HistoricalAwards=false
• 关键词: Effects; Reduced; Mechanical; Loading; Bone

Decreased physical activity can cause bone loss in many conditions, including long-term bed rest, weightlessness, and paralysis. The manifestations of this bone loss have been quantified primarily by assessing bone mass at a macroscale, above the level of the osteocyte, the most abundant bone cell. Osteocytes form an interconnected network throughout bone tissue, and when bone is mechanically loaded during physical activity, fluid in the small pores surrounding osteocytes is forced to flow. This load-induced fluid flow is believed to play a role in bone's biological response by translating whole body forces to the cellular. Recent studies demonstrate that the osteocyte can actively alter its local bone architecture. The research goal of this project is to investigate whether reduced mechanical loading causes the bone cells to alter the bone porosities and environment, such that bone's ability to detect mechanical loading is diminished. Such a disruption could be an important contributing factor to the overall degradation of bone strength in reduced loading conditions. Results from this work will make a significant contribution to understanding how reduced mechanical loading affects bone strength and may enable the development of targeted clinical approaches that eliminate the bone loss that occurs in disuse osteoporosis. In addition to supporting graduate students in the research, high school students will also be involved and new teaching modules will be created and incorporated into undergraduate classes.This work will assess bone microstructural and cellular-level changes due to a mechanical challenge of decreased loading. A rat disuse osteoporosis model will be used to investigate the effect of reduced mechanical loading on osteocyte-level parameters temporally using high-resolution microscopy. A non-invasive mechanical loading device will then be utilized to assess functional changes in interstitial fluid movement using injected tracers to quantify the effective osteocyte pericellular matrix pore size. High-resolution micro-CT analyses will also be performed to assess bone microarchitectural changes due to disuse, including vascular porosity changes. Then the microstructural measurements will be input into poroelastic models to calculate cellular-level strains for disuse and controls. The application of mechanical loading to counteract bone loss from disuse will also be evaluated to test whether tissue structure can be restored if osteocytes experience their usual mechanical input. By investigating the influence of in vivo mechanical forces on cell and matrix biology in the maintenance of bone tissue, this high-resolution experimental and computational study will yield important details about bone mechanotransduction.

在许多情况下，体育活动的减少会导致骨质流失，包括长期床休息，失重和瘫痪。这种骨质流失的表现主要是通过评估宏观骨骼质量（高于骨细胞水平，最丰富的骨细胞水平）的量子量化的。整个骨细胞在整个骨组织中形成一个相互联系的网络，当骨骼在体育活动中机械加载时，骨细胞周围的小孔中的液体被迫流动。据信这种负荷诱导的液体流通过将全身力转换为细胞，在骨骼的生物反应中起作用。最近的研究表明，骨细胞可以主动改变其局部骨结构。该项目的研究目标是研究减少机械负荷是否会导致骨细胞改变骨孔隙和环境，从而使骨骼检测机械负荷的能力降低。 这种破坏可能是减少负载条件下骨强度总体降解的重要因素。这项工作的结果将为了解减少的机械负荷如何影响骨骼强度做出重大贡献，并可以使靶向临床方法的发展开发，从而消除废弃骨质疏松症的骨质流失。除了支持研究生外，还将参与高中生，并将创建新的教学模块并将其纳入本科课程。由于负载减少的机械挑战，这项工作将评估骨微结构和细胞级变化。大鼠废除骨质疏松模型将用于研究使用高分辨率显微镜在时间上暂时的机械负荷对骨细胞级参数的影响。然后，将使用注射示踪剂来量化有效的骨细胞周围基质基质孔径来评估间质流体运动的功能变化。还将进行高分辨率的微CT分析，以评估由于废物而引起的骨微体系构造的变化，包括血管孔隙度变化。然后，微观结构测量将输入到毛弹性模型中，以计算用于废弃和对照的细胞水平菌株。还将评估机械载荷来抵消废弃的骨质流失，以测试如果骨细胞经历通常的机械输入，是否可以恢复组织结构。通过研究体内机械力对细胞和基质生物学在骨组织维持中的影响，这项高分辨率实验和计算研究将产生有关骨骼机械转导的重要细节。