Stimulating Bone Formation using constrained Tibial Vibration

描述（由申请人提供）：骨负荷是一种强大的骨合成代谢刺激物，有可能预防或逆转与骨质疏松症相关的骨丢失。全身振动的低振幅（< 1.0 g）、高频（> 20 Hz）负载具有特殊的临床意义，因为它可以作为被动、非侵入性刺激传递，副作用很少。使用全身振动的初步临床研究很有希望，但在显着增加骨密度方面并不一致，这表明需要进一步研究。此外，低振幅、高频率载荷刺激骨形成的机械生物学机制在很大程度上是未知的。在全身振动的背景下，这些机制的检查是复杂的，因为它可能很难控制在感兴趣的骨骼部位的局部刺激。因此，为了推进振动载荷如何刺激骨形成的科学并补充使用全身振动的平移研究，存在对能够更好地控制对感兴趣部位的振动刺激的模型系统的未满足的需求。我们设计了一种装置，将垂直振动载荷直接传递到小鼠的小腿，我们称之为“约束胫骨振动”的技术。我们在R21开发项目中的总体目标是表征小鼠胫骨对限制性胫骨振动的成骨反应。在目标1中，我们将确定在一系列旨在产生不同胫骨应变水平的条件下，胫骨对振动载荷的骨形成反应。我们将确定载荷响应是由于振动本身还是由于振动载荷引起的骨应变。在目标2中，我们将通过检查受限胫骨振动诱导的溶质转运和基因表达来评估分子反应。约束胫骨振动模型的成功开发将为具有靶向基因突变的小鼠的未来研究奠定基础，从而为检查骨骼对临床相关、低振幅、高频率载荷的反应的分子基础提供有力的工具。

DESCRIPTION (provided by applicant): Skeletal loading is a powerful osteoanabolic stimulus that has the potential to prevent or reverse the bone loss associated with osteoporosis. Low-amplitude (< 1.0 g), high- frequency (> 20 Hz) loading by whole-body vibration is of particular clinical relevance because it can be delivered as a passive, non-invasive stimulus with few side effects. Initial clinical studies using whole-body vibration have been promising but not uniformly successful in significantly increasing bone density, indicating a need for further investigation. Moreover, the mechanobiological mechanisms by which low-amplitude, high-frequency loading stimulate bone formation are largely unknown. Examination of these mechanisms is complicated in the context of whole-body vibration because it can be difficult to control the local stimulus at the skeletal site of interest. Thus, in order to advance the science of how vibrational loading stimulates bone formation and to complement translational studies using whole-body vibration, there is an unmet need for a model system that enables greater control of the vibrational stimulus to the site of interest. We have designed an apparatus to deliver vertical vibrational loading directly to the lower leg of the mouse, a technique we have termed "constrained tibial vibration". Our overall goal in this R21 developmental project is to characterize the osteogenic response of the murine tibia to constrained tibial vibration. In Aim 1, we will determine the bone formation response of the tibia to vibrational loading under a range of conditions designed to produce different levels of tibial strain. We will determine whether or not the loading response is due to vibration per se or due to bone strain induced by vibrational loading. In Aim 2, we will assess molecular responses by examining solute transport and gene expression induced by constrained tibial vibration. Successful development of the constrained tibial vibration model will establish a basis for future studies in mice with targeted genetic mutations, thus providing a powerful tool for examining the molecular basis of the skeletal response to clinically relevant, low- amplitude, high-frequency loading.