Stimulating Bone Formation using constrained Tibial Vibration

描述（由申请人提供）：骨骼负荷是一种强大的骨合成代谢刺激，具有预防或逆转骨质疏松症相关的骨质流失的潜力。低振幅（< 1.0 g），高频率（> - 20hz）的全身振动载荷具有特殊的临床意义，因为它可以作为一种被动的，非侵入性的刺激，几乎没有副作用。使用全身振动的初步临床研究很有希望，但在显著增加骨密度方面并不都是成功的，这表明需要进一步的研究。此外，低振幅，高频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，因为很难控制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研究，并补充使用全身振动的转化研究，需要一个能够更好地控制感兴趣部位的振动刺激的模型系统。我们设计了一种装置，将垂直振动载荷直接传递到老鼠的小腿，我们将这种技术称为“受限胫骨振动”。在这个R21发展项目中，我们的总体目标是表征小鼠胫骨对受限胫骨振动的成骨反应。在目的1中，我们将确定在一系列条件下胫骨对振动载荷的骨形成反应，这些条件旨在产生不同水平的胫骨应变。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。该受限胫骨振动模型的成功开发将为未来靶向基因突变小鼠的研究奠定基础，从而为研究骨骼对临床相关、低振幅、高频载荷反应的分子基础提供有力工具。

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.