Kick-starting mechanoadaptation in aged bones

动物可以改变单个肢骨的形状和质量，以适应习惯的和新的强加的机械力。这可能是最好的例子，在网球运动员的主要发球臂与非发球投球臂的骨量增加-我们将这些变化的过程称为机械适应。如果我们了解这种机械适应性骨量增加是如何协调的，我们就能模仿它们，从而减轻骨量的减少，从而使骨骼的特定区域处于骨折的危险之中。这种骨折的风险在老化的骨骼中是非常明显的，因为骨骼在外力作用下无法表现出这种结构改变的能力。这种不适应的后果是巨大的，往往是隐藏的，随着寿命的延长和生活方式的选择，这种后果正在急剧增加——对健康和社会的代价是巨大的。我们不了解骨力学适应是如何协调的一个主要原因。原因是，到目前为止，我们还不能将微观水平的骨弯曲与骨形成中随后结构增加的精确位置相匹配。我们最近取得的三项进展使这一切成为可能。我们已经开发了：i)一种非手术模型，可以对活老鼠的胫骨施加可控力；ii)一种测量小骨头整个表面弯曲程度的方法；iii)最近获得了一台机器，可以对骨骼活跃形成的位置进行精确的微观3D分析。这创造了一个独特而及时的机会。以前认为，机械适应过程的作用是最小化“最大”弯曲。我们已经生成了试点数据，使我们能够预测，相反，骨骼适应是为了最小化其表面上“最陡峭”的局部弯曲梯度。为了验证这一点，我们将在成熟的老鼠身上弯曲一些骨头，我们知道这些骨头会通过增加骨骼形成来适应。为了测试陡峭的弯曲梯度是否“驱动”形成，我们将：i)测量弯曲模式以生成横跨胫骨表面的“等高线图”，而胫骨受到机械力的影响；ii)生成整个胫骨的3D图像，准确描述骨形成的位置；iii)通过高功率3D x射线成像探索胫骨结构的整体变化，iv)创建由这些机械力引起的变化的虚拟数字计算机图像。这些研究将确定哪种特定的机械力负责促进骨形成，以及这种情况是否发生在弯曲梯度确实最陡峭的地方。这将是有用的，如果它可以用来修改骨骼不能履行其结构承重的作用，如老化。因此，我们从老年小鼠骨骼中获得的试验数据至关重要，因为它们表明弯曲梯度看起来不那么“陡峭”；由力引起的弯曲的一般幅度增加，因此最陡的梯度不那么严重。使用上述方法以及骨质量和细胞对机械刺激反应的测量，我们将探索老年小鼠胫骨是否表现出对弯曲力的细胞敏感性降低和/或能够促进适应的机械刺激减少。我们的初步研究还表明，衰老的小鼠骨骼不表现出机械适应性，有趣的是，这可以通过事先长时间不习惯使用而恢复到衰老的骨骼。我们建议探索这种修复变化的因素，希望我们能够确定如何启动老化骨骼的机械适应，从而减轻骨折的风险。以精确的3D方式定义新骨形成适应性增加的驱动因素，也将使未来的研究能够查明协调机械适应所必需的细胞事件。

Animals can modify the shape and mass of their individual limb bones to accommodate both habitual and new, imposed mechanical forces. This is perhaps best exemplified by the increases in bone mass that are seen in the dominant, serving arm of tennis players versus their non-serving, ball-throwing arm - we term the process by which these changes are achieved mechano-adaptation. If we understood the way such mechano-adaptive increases in bone mass were coordinated, we would be able to mimic them and, thus, alleviate any decreases in bone mass that places specific regions of bones at risk of fracture. This risk of fracture is very obvious in ageing bones, which fail to exhibit the capacity for such structural modification in response to imposed forces. There are massive, often hidden, consequences of such failure to adapt, which are increasing dramatically with enhanced longevity and lifestyle choices - the costs to health and society are huge. There is one main reason why we don't understand how bone mechano-adaptation is coordinated. The reason is that until now we have not been able to match microscopic level bone bending in response to imposed forces with the precise location of the ensuing structural increases in bone formation. We have recently made three advances that now make this possible. We have developed: i) a non-surgical model for imposing controllable forces to the tibia in living mice, ii) a means of measuring the extent of bending over the entire surface of small bones, and iii) recently acquired a machine that allows a precise microscopic 3D analysis of where bone is actively being formed. This creates a unique and timely opportunity. It was previously thought that mechano-adaptive processes acted to minimise the 'greatest' bending. We have generated pilot data that have allowed us to predict that, in contrast, bones adapt in order to minimise the 'steepest' local bending gradients on their surface. To test this we will bend some bones in mature mice that we know will adapt by increasing bone formation. To test whether steep bending gradients 'drive' formation we will: i) measure the bending pattern to generate a 'contour map' across the tibial bone surface, while it is being exposed to mechanical forces; ii) produce a 3D picture of the entire tibia describing exactly where bone formation takes place; iii) explore the overall changes in tibial structure by high-power 3D X-ray imaging, and iv) create virtual, digital computer images of the changes induced by these mechanical forces. These studies will determine which specific mechanical force is responsible for promoting bone formation and whether this occurs where bending gradients are indeed steepest. This will be useful if it can be used to modify bones which fail to fulfil their structural load-bearing role, as in ageing. Our pilot data from aged mouse bone are therefore crucial as they show that bending gradients appear less 'steep'; the general magnitude of bending engendered by force increases and the steepest gradients are consequently less severe. Using the methods described above as well as measures of bone quality and cellular responses to mechanical stimulation, we will explore if tibiae in aged mice exhibit a reduced cellular sensitivity to bending forces and/or a reduced mechanical stimulus capable of promoting adaptation. Our pilot studies have also shown that aged mouse bones do not exhibit mechano-adaptation and, intriguingly, that this can be restored to aged bones by prior imposition of a prolonged period without habitual use. We propose to explore the factors that change with this restoration, in the hope that we can identify how to kick-start mechano-adaptation in aged bones and thus alleviate the risk of fracture. Defining the drivers of adaptive increases in new bone formation in a precise 3D manner will also allow future studies to pinpoint the cellular events that are necessary to coordinate mechano-adaptation.