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

基本信息

批准号：
8628047
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
项目类别：
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/8628047
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 Factor 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 public health relevance restoration second messenger signal processing skeletal skeletal disorder

项目摘要

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）：低骨量的疾病，例如依赖年龄的骨质疏松症，对社会产生了深远的影响。当前的骨骼恢复或维持的疗法受到限制，主要集中于破骨细胞活性的衰减。 GAP连接蛋白连接43允许在成骨细胞和骨细胞之间进行信号的直接细胞对电池通信，已显示在成骨细胞/骨细胞功能以及峰值骨量的获取中起重要作用。尽管连接蛋白43在骨骼功能中显然重要，但连接蛋白43如何调节骨骼质量的关键细节，成骨细胞分化和成骨细胞/骨细胞功能尚不清楚。不理解影响骨骼质量习得的潜在分子机制，无法设计影响骨骼疾病的理性疗法，例如骨质疏松症。实际上，任何旨在影响整个骨骼形成单元以逆转或减慢骨骼疾病的干预措施都需要了解信息的细胞间交换方法，例如连接蛋白43在成骨细胞和成骨细胞中提供的信息，以获得最佳效率。在此赠款应用中，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的分化和功能，并最终调节骨质质量，从而融合了成骨细胞生成的主要调节剂Runx2和iosterix。该赠款有两个具体的目的来解决这一假设。（特定目的1）确定在Runx2和/或Osterix水平上CX43和CX43依赖性信号对成骨分化的贡献；（特定目的2）确定通过连接蛋白43募集信号复合物对连接蛋白43和第二信使渗透性的要求，以便下游调制成骨分化和信号传导。我们将使用细胞和分子生物学以及体内遗传模型来解决关键知识差距，涉及连接蛋白43如何调节骨骼。通过定义这些机制，我们将对连接蛋白43最终如何影响成骨细胞功能和骨质量获取的方式有批判性了解。的确，我们的长期目标是将这些研究收集的知识应用于结合蛋白43表达或连接蛋白43依赖性信号传导级联反应，无论是生理上还是药理上，以增加骨质量的获取，以预防或治疗骨骼脆弱性的疾病。确实，了解成骨细胞，骨细胞和破骨细胞网络的协调对于几乎所有骨骼代谢的疾病的理解至关重要。