Regulation of Osteoblast Differentiation and Function by Connexin 43

连接蛋白 43 对成骨细胞分化和功能的调节

• 批准号: 9022410
• 负责人: Joseph P. Stains
• 金额: $ 32.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022410
• 关键词: Ablation; Acute; Address; Affect; Aging; Applications Grants; Biological Assay; Biology; C-terminal; Calvaria; Cell Communication; Cells; Cellular biology; Complex; Connexin 43; Connexins; Defect; Deposition; Development; Diffusion; Disease; Extracellular Matrix; Gap Junctions; Gene Expression; Genes; Genetic; Genetic Models; Glean; Goals; Grant; Growth; Health; Hereditary Disease; Hormonal; Impairment; Intervention; Knock-out; Knowledge; Maintenance; Mechanics; Metabolic Bone Diseases; Metabolism; Methods; Modeling; Molecular; Molecular Biology; Molecular Target; Mus; Names; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Paracrine Communication; Participant; Pathway Analysis; Pathway interactions; Peptides; Permeability; Phenotype; Play; Point Mutation; Population; Postmenopausal Osteoporosis; Property; Recruitment Activity; Regulation; Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skeleton; Societies; Tail; Testing; age related; attenuation; bone; bone cell; bone mass; bone quality; combat; connexin 45; design; in vivo; intercellular communication; mutant; novel; oculodentodigital dysplasia; osteoblast differentiation; osteogenic; osteoprogenitor cell; overexpression; prevent; restoration; second messenger; signal processing; skeletal; skeletal disorder

DESCRIPTION (provided by applicant): Diseases of low bone mass, like age-dependent osteoporosis, have a profound impact on society. Current therapies for the restoration or maintenance of bone mass are limited and focus primarily on the attenuation of osteoclast activity. The gap junction protein connexin 43, which permits the direct cell-to-cell communication of signals between osteoblasts and osteocytes, has been shown to play an important role in osteoblast/osteocyte function and the acquisition of peak bone mass. Despite the clear importance of connexin 43 in skeletal function, key molecular details of how connexin 43 regulates bone mass acquisition, osteoblast differentiation and osteoblast/osteocyte function are unknown. Rational therapies to impact skeletal diseases, like osteoporosis, cannot be designed without understanding the underlying molecular mechanisms affecting bone mass acquisition. Indeed, any intervention intended to impact the entire bone forming unit to reverse or slow down skeletal diseases will require an understanding of the intricate methods of intercellular exchange of information, such as those afforded by connexin 43, among osteoblasts and osteocytes for optimal efficacy. In this grant application, we hypothesize that connexin 43 regulates osteogenic differentiation and function, and ultimately bone quality, by regulating the recruitment and activation of signal transduction cascades that converge upon the master regulators of osteoblastogenesis, Runx2 and Osterix. This grant has two specific aims to address this hypothesis. (Specific Aim 1) To determine the contribution of Cx43 and Cx43-dependent signaling to osteogenic differentiation at the level of Runx2 and/or Osterix; (Specific Aim 2) To determine the requirements for both signal complex recruitment to connexin 43 and second messenger permeability by connexin 43 for downstream modulation of osteogenic differentiation and signaling. We will use cell and molecular biology, as well as in vivo genetic models to resolve key knowledge gaps, regarding how connexin 43 regulates bone. By defining these mechanisms, we will gain critical understanding of how connexin 43 ultimately affects osteoblast function and bone mass acquisition. Indeed our long-term goal is to apply the knowledge gleaned from these studies to modulate connexin 43 expression or connexin 43-dependent signaling cascades, either physiologically or pharmacologically, to increase bone mass acquisition to prevent or treat diseases of skeletal fragility. Indeed, understanding the coordination of osteoblast, osteocyte and osteoclasts networks is vital to the understanding nearly all diseases of skeletal metabolism.

描述（由申请人提供）：低骨量疾病，如年龄依赖性骨质疏松症，对社会产生深远影响。目前用于恢复或维持骨量的疗法是有限的并且主要集中于破骨细胞活性的减弱。间隙连接蛋白连接蛋白 43 允许成骨细胞和骨细胞之间直接进行细胞间信号通讯，已被证明在成骨细胞/骨细胞功能和峰值骨量的获得中发挥重要作用。尽管连接蛋白 43 在骨骼功能中具有明显的重要性，但连接蛋白 43 如何调节骨量获取、成骨细胞分化和成骨细胞/骨细胞功能的关键分子细节尚不清楚。如果不了解影响骨量获得的潜在分子机制，就无法设计影响骨质疏松症等骨骼疾病的合理疗法。事实上，任何旨在影响整个骨形成单位以逆转或减缓骨骼疾病的干预措施都需要了解成骨细胞和骨细胞之间细胞间信息交换的复杂方法，例如连接蛋白 43 提供的方法，以获得最佳功效。在这项资助申请中，我们假设连接蛋白 43 通过调节信号转导级联的募集和激活来调节成骨分化和功能，并最终调节骨质量，这些信号转导级联汇聚于成骨细胞生成的主调节因子 Runx2 和 Osterix 上。这笔赠款有两个具体目标来解决这一假设。 （具体目标1）确定Cx43和Cx43依赖性信号传导对Runx2和/或Osterix水平的成骨分化的贡献； （具体目标 2）确定信号复合物募集到连接蛋白 43 和连接蛋白 43 的第二信使渗透性对成骨分化和信号转导下游调节的要求。我们将利用细胞和分子生物学以及体内遗传模型来解决有关连接蛋白 43 如何调节骨骼的关键知识空白。通过定义这些机制，我们将获得对连接蛋白 43 最终如何影响成骨细胞功能和骨量获取的批判性理解。事实上，我们的长期目标是应用从这些研究中收集的知识来调节连接蛋白 43 表达或连接蛋白 43 依赖性信号级联，无论是生理学还是药理学，以增加骨量获取，以预防或治疗骨骼脆弱疾病。事实上，了解成骨细胞、骨细胞和破骨细胞网络的协调对于了解几乎所有骨骼代谢疾病至关重要。