Augmentation of Peak Bone Mass

与骨质疏松性骨折相关的主要危险因素之一是在成年早期未能获得足够的骨量。运动对非侵入性骨质增生具有巨大的潜力，但一般的运动方案只能在正常水平上最低限度地提高骨量，并且依赖于高冲击、高强度的负荷来实现这些骨质增加。最近，我们发现在低强度加载方案的每个加载周期之间插入一个短暂的休息间隔足以将方案从一个不影响骨细胞群的方案转变为一个潜在的成骨信号。因此，这种方案可能特别适用于需要增强骨性能的情况，但高强度运动是不可行的。基于我们的初步数据和对文献的回顾，我们假设在骨骼生长过程中开始的低强度、休息插入、机械载荷将增强成年哺乳动物的皮质骨特性。为了探索这一假设，我们将利用我们最近开发的非侵入性小鼠胫骨加载装置。在雌性C57BLI6J小鼠中，我们设计了一系列的5个特异性目的来确定置入休息物、低强度负荷是否有助于建立和维持增强的胫骨皮质骨特性。研究以我们的最终目标为结束，我们将评估rest插入负载诱导的皮质骨特性增强是否足以抵消衰老和雌激素消耗引起的退化。在基本层面上，这些研究将为年轻骨骼对机械负荷的反应提供独特的见解，并将提供一个基线信息，我们将在未来开始探索特定的遗传改变（例如，通过转基因或敲除小鼠）如何影响骨骼的机械转导。在应用层面，置入支架、低强度、非侵入性载荷显著增强和维持小鼠皮质骨特性的结果将使我们的研究小组开始探索这一概念在人类受试者中的功效。

One of the primary risk factors associated with osteoporotic fractures is the failure to achieve sufficient bone mass during early adulthood. Exercise holds substantial potential for non-invasive bone accretion, but general exercise protocols only minimally enhance bone mass over normal levels and rely upon high impact, high magnitude loading to achieve these bone gains. Recently, we found that inserting a brief rest interval between each load cycle of a low magnitude loading regimen is sufficient to transform the protocol from one that does not influence bone cell populations into a signal that is potently osteogenic. This regimen may therefore be particularly amenable to application in conditions where enhanced bone properties are desirable, but high impact exercise is not feasible. Based upon our preliminary data and a review of the literature, we hypothesize that low magnitude, rest-inserted, mechanical loading initiated during skeletal growth will enhance the cortical bone properties of adult mammals. To explore this hypothesis, we will capitalize on our recently developed non-invasive murine tibia loading device. A series of five Specific Aims have been designed to determine if rest-inserted, low magnitude loading can serve to build and maintain augmented tibial cortical bone properties in female C57BLI6J mice. The studies culminate with our final Aim, in which we will assess whether enhanced cortical bone properties induced by the rest-inserted loading are sufficient to counteract the degradation caused by aging and estrogen depletion. At a basic level, these studies will provide unique insight toward how young growing bones respond to mechanical loading, and will provide a baseline of information from which we will, in the future, begin to explore how specific genetic alterations (e.g., via transgenic or knockout mice) affect mechanotransduction in bone. At the applied level, an outcome in which rest-inserted, low magnitude, non-invasive loading significantly augments and maintains murine cortical bone properties would place our group in position to begin to explore the efficacy of this concept in human subjects.