Structural, Molecular, and Functional Specialization in Osteocyte Mechanosensing

骨细胞机械传感的结构、分子和功能专业化

基本信息

批准号：
8139065
负责人：
MITCHELL B SCHAFFLER
金额：
$ 50.29万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-06 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139065
关键词：
Address Aging Anabolic Agents Biochemical Biomechanics Biomedical Engineering Bone Matrix Bone Tissue Cell physiology Cells Complex Development Dinoprostone Disease Engineering Environment Estrogens Failure Fracture Gap Junctions Goals Gonadal Steroid Hormones Grant Health In Situ In Vitro Individual Integrins Investigation Ion Channel Laboratories Lead Liquid substance Measures Mechanical Stimulation Mechanics Mediating Medicine Membrane Methods Modeling Molecular Osteocytes Outcome Pathway interactions Physiology Process Prostaglandin E Receptor Resolution Signal Transduction Site Stimulus Stress Structure System Technology Testing Theoretical model Time Tissues Translating autocrine base bone bone cell bone loss cell type college design detector experience fluid flow in vitro Model in vivo insight interdisciplinary approach mathematical model neuronal cell body new technology new therapeutic target novel prevent programs public health relevance research study response sensor shear stress skeletal theories voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Osteocytes, the cells that reside within bone matrix, are the most abundant bone cells. They function as the mechanical sensors in bone, and are critical to activation and coordination of osteoclastic and osteoblastic activities by which bone adapts to mechanical usage, maintains its health and prevents fractures. The mechanisms underlying osteocyte mechanotransduction are not well understood, though changes osteocyte mechanosensitivity have been implicated in regulating the effect of both bone anabolic agents and sex hormones. We have developed engineering models which show that small whole bone strains can be amplified locally around osteocyte processes by focal attachments to the canalicular wall. Osteocyte cell bodies cannot see similar high strains as they are too compliant and lack the cellular attachments needed for local strain amplification. These mathematical models argue that the osteocyte cell process may be uniquely designed to function as a detector of small tissue strains. To test this hypothesis, we developed a broad-based multiple-PI program that combines expertise in ion channel physiology, in vivo osteocyte structure/biomechanics and bioengineering/modeling to understand how osteocytes perceive and transduce their local mechanical environment. This program will a) examine the functional polarity of osteocyte mechano- responsiveness using electrophysiological approaches on cultured osteocytes (Aim 1), b) identify the molecular components of mechanotransduction complexes in osteocytes (Aim 2), c) characterize the structure of the mechanotransduction complex in osteocytes in vivo (Aim 3) and d) build integrative mathematical models relating local hydrodynamic forces and membrane strains at osteocyte processes and cell bodies to cellular responses in vitro and in vivo (Aim 4). We have also developed a novel technology ("Stokesian" Fluid Stimulus probe) that allows us to hydrodynamically load osteocyte processes vs. cell bodies at extremely low forces (<10pN) typical of what bone cells actually experience in vivo. Expansion of this technology to interrogate mechano-responsiveness in a broad range of cell types is a developmental goal of this grant. Significance: Understanding how osteocytes "perceive" and transduce mechanical signals may provide key new insights into bone physiology leading to the identification of novel therapeutic targets against bone loss due to aging and disease. PUBLIC HEALTH RELEVANCE: Osteocytes are the cells in bone that sense mechanical loading and translate mechanical strain into biochemical signals that initiate modeling and remodeling through which bone adapts its structure to its mechanical loading environment. This ability is key to skeletal health; failure to adapt results in bone in fragility. Increases and decreases in osteocyte mechanosensitivity have been implicated in regulating the bone response to anabolic agents, and conversely the bone loss resulting from estrogen loss, respectively. Thus understanding how osteocytes "perceive" and transduce mechanical signals may provide key new insights into bone physiology leading to the identification of novel therapeutic targets against bone loss due to aging and disease.

描述（由申请人提供）：骨细胞（居住在骨基质中的细胞）是最丰富的骨细胞。它们充当骨骼中的机械传感器，对于整骨和成骨细胞活性的激活和协调至关重要，骨骼可适应机械使用，保持其健康状况并防止骨折。尽管变化的变化与调节骨合成代谢剂和性激素的作用有关，但骨质细胞机械敏感的变化与骨细胞机械敏感有关，但骨质细胞机械敏感性的变化尚未充分了解。我们已经开发了工程模型，这些模型表明，可以通过焦点附着在骨细胞过程的局部扩增整个整个骨骼，并通过对骨细胞的过程进行扩增。骨细胞细胞体无法看到相似的高应变，因为它们太顺从，并且缺乏局部应变扩增所需的细胞附着。这些数学模型认为，骨细胞细胞过程可能是独特的，以充当小组织菌株的检测器。为了检验这一假设，我们开发了一个基于广泛的多重PI程序，该程序结合了离子通道生理学，体内整骨细胞结构/生物力学和生物工程/建模的专业知识，以了解骨细胞如何感知和传递其本地机械环境。 This program will a) examine the functional polarity of osteocyte mechano- responsiveness using electrophysiological approaches on cultured osteocytes (Aim 1), b) identify the molecular components of mechanotransduction complexes in osteocytes (Aim 2), c) characterize the structure of the mechanotransduction complex in osteocytes in vivo (Aim 3) and d) build integrative mathematical模型在骨细胞过程和细胞体的局部流体动力和膜菌株与体外和体内的细胞反应有关（AIM 4）。我们还开发了一种新颖的技术（“ Stokesian”液体刺激探针），该技术使我们能够以极低的力（<10pn）（<10pn）在体内实际经历的骨细胞（<10pn）的细胞体加载骨细胞过程。扩展这项技术以在广泛的细胞类型中询问机械响应性是该赠款的发展目标。意义：了解骨细胞如何“感知”和跨性机械信号可以为骨骼生理学提供关键的新见解，从而鉴定出由于衰老和疾病而导致骨质流失的新型治疗靶标。公共卫生相关性：骨细胞是骨骼中的细胞，将机械负载并将机械拉力转化为生化信号，从而启动建模和重塑，骨头将其结构适应其机械负载环境。这种能力是骨骼健康的关键。无法适应脆弱性骨骼的结果。骨细胞机械敏感的增加和减少与调节对合成代谢剂的骨反应有关，相反，雌激素流失造成的骨质流失。因此，了解骨细胞如何“感知”和转导机械信号可以为骨骼生理学提供关键的新见解，从而鉴定出由于衰老和疾病而导致骨质流失的新型治疗靶标。