Osteocyte-independent mechanotransducation of interstitial fluid flow in bone

骨间质液流的骨细胞依赖性机械转导

• 批准号: 7615229
• 负责人: Ronald Y Kwon
• 金额: $ 4.52万
• 依托单位: LA JOLLA BIOENGINEERING INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615229
• 关键词: Ablation; American; Biomechanics; Bone Density; Bone Resorption; Bone remodeling; Cells; Cellular Mechanotransduction; Devices; Diphtheria Toxin; Environment; Esthesia; Femur; Goals; Health; Hindlimb; Hindlimb Suspension; Histologic; Intercellular Fluid; Measurement; Mechanics; Mediating; Microfluidic Microchips; Morphology; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Pharmacological Treatment; Process; Public Health; Recovery; Resistance; Risk; Role; Specific qualifier value; Structure; Surface; Tissues; Transgenes; Transgenic Mice; base; bone; bone cell; bone loss; diphtheria toxin receptor; fluid flow; indexing; insight; mouse model; novel; pressure; progenitor; response; skeletal; therapy development

DESCRIPTION (provided by applicant): A large body of evidence suggests that skeletal interstitial fluid flow (IFF) mediates bone remodeling in response to mechanical loading. Our long-term goal is to develop treatments for bone loss based on bone cell mechanotransduction of IFF. A crucial step towards this goal is to understand how the responses of bone cells exposed to IFF result in bone remodeling. Recently, Tatsumi and colleagues generated a transgenic mouse model with inducible osteocyte ablation. Interestingly, although these mice were resistant to bone loss upon hindlimb suspension, mechanotransduction in these mice upon reloading was normal. This gives rise to the intriguing possibility that while osteocytes regulate IFF-mediated bone loss, increases in IFF during reloading may induce bone formation by direct stimulation of other types of bone cells. Our central hypothesis is that IFF mediates the bone resorption and formation that occur during unloading and reloading by two distinct mechanisms. During unloading, lack of IFF results in osteocyte- mediated bone resorption. During reloading, increased IFF induces bone formation by direct stimulation of osteoblasts or their progenitors. Recently, our lab has developed a novel microfluidic device for generating dynamic IFF in the femurs of hindlimb suspended mice. The device will be used to determine the role of osteocytes in mediating flow-induced bone remodeling within a native tissue environment. Specifically, we will first induce IFF in hindlimb suspended mice with and without ablated osteocytes to determine the capacity of IFF to inhibit osteoclastic activity upon disuse, and the role of osteocytes in mediating this process (aim 1). Next, by imposing a period of hindlimb suspension pre-osteocyte ablation, we will determine the capacity of IFF to stimulate recovery of disuse-induced bone loss in osteocyte-deficient mice (aim 2). Our findings will reveal fundamental insight into the cellular mechanisms involved in IFF-regulated bone remodeling and will represent a considerable advancement towards development of therapies for bone loss based on mechanotransduction of IFF. Relevance to Public Health: Osteoporosis is a major health risk for 28 million Americans. This study will reveal fundamental insight into how different cells within bone coordinate their responses to drive bone remodeling in response to interstitial fluid flow. Our findings will represent a considerable advancement towards development of therapies for bone loss based on the capacity of bone cells to sense and respond to fluid flow.

描述(申请人提供)：大量证据表明，骨骼间质液体流动(IFF)介导了骨重建对机械负荷的反应。我们的长期目标是开发基于IFF的骨细胞机械转导的骨丢失治疗方法。迈向这一目标的关键一步是了解暴露于IFF的骨细胞如何反应导致骨重建。最近，TatSumi和他的同事建立了一个可诱导的骨细胞消融的转基因小鼠模型。有趣的是，尽管这些小鼠对后肢悬吊时的骨丢失有抵抗力，但这些小鼠在重新加载时的机械转导是正常的。这提出了一种有趣的可能性，即在骨细胞调节IFF介导的骨丢失的同时，在重新加载过程中IFF的增加可能通过直接刺激其他类型的骨细胞来诱导骨形成。我们的中心假设是，IFF通过两种不同的机制来调节卸载和再加载过程中发生的骨吸收和骨形成。在卸载过程中，缺乏IFF会导致骨细胞介导的骨吸收。在重新加载过程中，增加的IFF通过直接刺激成骨细胞或其前体细胞诱导骨形成。最近，我们实验室开发了一种新型的微流控装置，用于在后肢悬吊小鼠的股骨中产生动态IFF。该装置将被用来确定骨细胞在自然组织环境中介导流动诱导的骨重建中的作用。具体地说，我们将首先在有和没有去除骨细胞的后肢悬吊小鼠中诱导IFF，以确定IFF在废弃时抑制破骨细胞活动的能力，以及骨细胞在这一过程中的中介作用(目标1)。接下来，通过施加一段时间的后肢悬吊前骨细胞消融，我们将确定IFF刺激骨细胞缺陷小鼠因废用而导致的骨丢失恢复的能力(目标2)。我们的发现将揭示IFF调控骨重建的细胞机制，并将代表着基于IFF机械转导的骨丢失治疗方法的发展的相当大的进步。与公共健康相关：骨质疏松症是2800万美国人的主要健康风险。这项研究将揭示骨内不同细胞如何协调它们的反应，以驱动骨重建对间质液体流动的响应。我们的发现将代表着基于骨细胞对液体流动的感知和反应能力的骨丢失治疗方法的开发取得了相当大的进步。