Osteocyte Control of Osteoblast Dynamics with Aging

骨质疏松症和肌肉减少症是骨和肌肉损失的疾病，代表了主要的临床问题 在老年人口中。这些情况经常一起发生，提示共同的致病机制 和/或肌肉和骨骼之间的串扰。骨质疏松症的当前治疗目标是破骨细胞或 成骨细胞活性维持骨量，但骨细胞一直被忽视。令人兴奋的最新研究 骨细胞是成骨细胞和破骨细胞功能的主要调节者， 骨细胞Wnt/3-catenin信号通路可能在骨质量调节中起重要作用。本实验室 采用了一种独特的方法，使用荧光实时成像检查成骨细胞-骨细胞相互作用 骨细胞和器官培养模型的方法。我们已经证明，骨表面的成骨细胞是 活成骨细胞中ECM蛋白的组装是一个高度动态的过程， 与细胞运动相结合。我们还表明，骨细胞产生的硬化蛋白和Wnt， 改变成骨细胞运动和分化功能。在这些观察的基础上，本项目将研究 从动态角度看骨细胞对成骨细胞功能的控制。总的假设是， 骨细胞通过Wnt/β-连环蛋白信号通路调节骨量， 成骨细胞的特性和分化功能，这种调节过程是由肌肉调节的， 骨串扰，并在老化过程中受损，导致骨骼受损。为了解决这个假设， 活细胞成像技术将用于表达荧光标记的年轻和老年转基因小鼠模型， 成骨细胞和骨细胞谱系的报告基因和GFP标记的细胞外基质蛋白。的影响 骨细胞产生的Wnt和硬化蛋白的调节将使用抑制剂、基因沉默和 转基因方法确定肌肉的串扰是否改变成骨细胞对成骨细胞的控制 功能，在成肌细胞分化的体外模型和受损或增强的转基因和老年模型中， 将使用肌肉功能。这些研究可能会导致新的治疗方法， 防止老年人骨质和肌肉质量的流失。 相关性（见说明）： 骨质疏松症和肌肉减少症是老年人经常同时发生的骨骼和肌肉损失疾病 这是一个严重的公共卫生问题。本研究的目的是确定 分子和细胞机制，有助于这些条件的协调发展。这 研究可能会导致这些疾病的新的治疗方法的发展。

Osteoporosis and Sarcopenia are diseases of bone and muscle loss that represent a major clinical problem in the aged population. These conditions often occur together, suggesting common pathogenic mechanisms and/or crosstalk between muscle and bone. Cunent treatmente for osteoporosis target osteoclast or osteoblast activity to maintain bone mass, but tiie osteocyte has been overiooked. Exciting recent research has shown that osteocytes are major regulators of osteoblast and osteoclast function and that regulation of the Wnt/3-catenin pathway by osteocytes may play a central role inregulationof bone mass. Our laboratory has taken a unique approach to examining osteoblast-osteocyte interactions using fiuorescence live imaging approaches in bone cell and organ culture models. We have shown that osteoblasts on the bone surface are motile cells and that assembly of ECM proteins In living osteoblasts is a highly dynamic process that is integrated with cell motility. We have also shown that Sclerostin and Wnts, both produced by osteocytes, can alter osteoblast motility and differentiated function. Building on these observations, this project will examine osteocyte control of osteoblast function from a dynamic perspective. The overall hypothesis is that osteocytes regulate bone mass through the Wnt/p-catenin signaling pathway by controlling the motile properties and differentiated function of osteoblasts and that this regulatory process is modulated by muscle- bone crosstalk and is impaired during aging, leading to a compromised skeleton. To address this hypothesis, live cell imaging techniques will be used in young and aged transgenic mouse models expressing fluorescent reporters for osteoblast and osteocyte lineages and GFP-tagged extracellular matiix proteins. The effect of modulation of osteocyte-produced Wnt and sclerostin will be investigated using inhibitors, gene silencing and transgenic approaches. To determine whether crosstalk from muscle alters osteocyte control of osteoblast function, in viti-o models of myoblast differentiation and transgenic and aged models of impaired or enhanced muscle function will be used. These studies may lead to the way to novel therapeutic approaches for preventing loss of bone and muscle mass in the elderiy. RELEVANCE (See Instnictions): Osteoporosis and sarcopenia are diseases of bone and muscle loss that often occur togetiier in the aged population and represent a major public health problem. The goal ofthis research is to determine the molecular and cellular mechanisms that contribute to the co-ordinated development of these conditions. This research may lead to development of new treatment approaches for these diseases.