Advanced imaging to understand bone's adaptation to mechanical load

骨是一种动态组织，它根据接收到的信号通过增加或减少骨骼来响应环境。这些信号可以包括机械性的（例如，运动引起的负荷）和炎症性的（例如，受伤引起的肿胀）。尽管已经研究了骨骼对运动和其他形式负荷的反应，但骨骼如何在复杂环境中随着机械和炎症信号的变化而变化还不是很清楚。计算机断层扫描（CT）和磁共振成像（MRI）等成像技术的进步意味着我们现在能够同时研究活着的人和动物的骨骼和骨骼周围的组织，并且可以更好地捕捉骨骼随时间的变化。这意味着我们可以更好地了解骨骼如何以及为什么会因运动或卧床等活动而发生变化，以及骨骼如何与周围组织相互作用。我的研究计划的长期目标是开发和应用先进的成像技术，以更好地了解骨骼适应机械信号的机制。提出的工作将使用新的成像技术，使用微型计算机断层扫描（micro-CT，骨骼成像的理想选择），MRI（软组织成像的理想选择）和3D图像配准来测试关于骨适应定量测量中机械负荷和炎症之间相互作用的新假设。在这个为期五年的资助过程中，我的目标是应用3D图像配准技术来量化骨与软组织相互作用部位的骨形成和吸收，以评估骨体积和微结构随时间的变化。我将在骨-软组织相互作用的两个点上研究两种动物模型中的骨适应：1)在小鼠肌肉废用模型中的肌肉附着部位，2)在豚鼠关节边缘形成骨刺或骨赘，以验证骨对机械刺激的局部反应是由与软组织（如肌肉、韧带和软骨）的机械相互作用紧密介导的，而更远处的反应主要由炎症途径控制。在小鼠模型中，我将通过注射肉毒杆菌毒素诱导肌肉废用来操纵机械负荷，而在豚鼠模型中，我将通过前交叉韧带横断改变关节稳定性来操纵机械负荷。我会用消炎药扰乱炎症环境。这项工作将提高我们测量活体动物骨骼变化的能力，并确定炎症是否主导肌肉附着部位附近和远处的骨质流失以及关节损伤后骨刺的形成。该研究计划的发现将提高对驱动骨形成和骨吸收的刺激的理解，并将对促进人类骨形成具有重大意义。

Bone is a dynamic tissue that changes in response to its environment by adding or removing bone depending on the signals it receives. These signals can include mechanical (e.g., loading through exercise) and inflammation (e.g., swelling from an injury). Although bone's response to exercise and other forms of loading have been studied, how bone changes in complex environments with changing mechanical and inflammatory signals is not well understood. Advances in imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) mean that we are now able to study bone and the tissues around bone in living people and animals at the same time, and can better capture changes in bone over time. This means that we can develop a better understanding of how and why bone changes in response to activities such as exercise or bedrest, and how bone interacts with tissues surrounding it. The long-term goal of my research program is to develop and apply advanced imaging techniques to better understand the mechanism by which bone adapts to mechanical signals. The proposed work will use novel imaging techniques using micro-computed tomography (micro-CT, ideal for bone imaging), MRI (ideal for soft tissue imaging) and 3D image registration to test new hypotheses regarding the interaction between mechanical loading and inflammation on quantitative measures of bone adaptation. Over the course of this five year grant, my objective is to apply 3D image registration techniques to quantify bone formation and resorption at sites of interaction between bone and soft tissue to evaluate changes in bone volume and microarchitecture over time. I will examine bone adaptation in two animal models at two points of bone-soft tissue interaction: 1) muscle attachment sites in a well-established muscle disuse model in mice, and 2) bony spur, or osteophyte, formation at the edges of joints in guinea pigs to test the hypothesis that bone's local response to mechanical stimuli is tightly mediated by mechanical interaction with soft tissues such as muscle, ligament and cartilage, while the more distant response is controlled primarily by inflammatory pathways. In the mouse model, I will manipulate mechanical loading by inducing muscle disuse via botulinum toxin injection, while in the guinea pig I will manipulate mechanical loading by altering joint stability via anterior cruciate ligament transection. I will perturb the inflammatory environment using anti-inflammatory drugs. The proposed work will enhance our ability to measure bone changes in living animals, and determine whether inflammation dominates bone loss close to and far from muscle attachment sites as well as bone spur formation after joint injury. The findings from the proposed research program will improve understanding of the stimuli that drive bone formation and resorption, and will have substantial implications for enhancing bone formation in humans.