Connexin 43 Hemichannels and Signaling In Bone

Connexin 43 半通道和骨信号传导

基本信息

批准号：
8241176
负责人：
Lilian Irene Plotkin
金额：
$ 31.57万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241176
关键词：
Anabolism Apoptosis Apoptotic Arrestins Biological Preservation Bone Mineral Contents Bone remodeling Cell Communication Cell Nucleus Cell membrane Cells Clathrin Communication Complex Connexin 43 Connexins Cyclic AMP Defect Dinoprostone Disease Embryo Environment Failure Fracture Functional disorder G-Protein-Coupled Receptors Gap Junctions Gene Expression Gene Expression Regulation Glucocorticoids Health Hormonal Hormones In Vitro Inhibition of Apoptosis Knockout Mice Maintenance Mechanical Stimulation Mechanics Mediating Membrane Proteins Mitogen-Activated Protein Kinases Mus Nuclear Osteoblasts Osteoclasts Osteocytes Osteogenesis Parathyroid gland Pathway interactions Phosphotransferases Prevention Production Property Protein Family Role Scaffolding Protein Signal Pathway Signal Transduction Skeleton Stimulus Testing Thick Time Tissues Wild Type Mouse Work analog base bisphosphonate bone bone cell bone strength extracellular gap junction channel improved in vivo novel prevent response scaffold tool

项目摘要

DESCRIPTION (provided by applicant): Connexins (Cx) are a family of proteins essential for cell-to-cell communication and for the communication of cells with their environment. Cx43 is the most abundant connexin expressed in bone cells. The importance of Cx43 expression in the skeleton has been established by the demonstration of the osteoblast dysfunction and delay ossification in embryos of Cx43 null mice. However, the role of Cx43 and, in particular Cx43 hemichannels expressed in unopposed cell membranes, is far from being completely understood. In studies leading to this application it was demonstrated that bisphosphonates, besides stopping osteoclast-mediated resorption, might preserve bone strength at least in part by promoting osteoblast and osteocyte viability and that Cx43 expression is required for this survival effect. Thus, inhibition of apoptosis by bisphosphonates requires opening of Cx43 hemichannels, activation of the extracellular signal-regulated kinases (ERKs) and extra-nuclear retention of the kinases due to their interaction with the scaffolding protein (-arrestin. Cx43 is also required for prevention of osteoblast apoptosis by parathyroid hormone (PTH) in vitro; and the anabolic response to intermittent administration of the hormone is blunted in mice deficient mice in Cx43. In addition, Cx43 might be also involved in mechanotransduction in the skeleton. Thus, mechanical stimulation increases Cx43 expression, gap junction communication and hemichannel opening in osteoblasts and osteocytes. Based on this evidence, it is hypothesized that Cx43 is a crucial component of signaling pathways activated by pharmacologic, hormonal and mechanical stimuli in osteoblasts and osteocytes, via its involvement in hemichannels or gap junctions or its scaffolding properties. This hypothesis will be tested by a combination of in vitro and in vivo approaches. Studies in Aim 1 will examine the in vivo relevance of the Cx43/(-arrestin/ERK pathway for bisphosphonate actions on bone using bisphosphonate analogs that selectively activate this pathway; and they will delineate the mechanism by which association of Cx43, ERKs and (-arrestin leads to retention of ERKs outside the nucleus and the internalization of Cx43. Studies in Aim 2 will determine the role of Cx43 in the anti-apoptotic effect of PTH in vivo by examining whether the lack of anabolic effect of intermittent PTH administration to mice deficient in Cx43 is due to the inability of PTH to prevent osteoblast apoptosis. Aim 3 will define the role of Cx43 hemichannels in mechanotransduction in vivo and in vitro. This will be accomplished by investigating whether changes in gene expression and the anabolic response to mechanical loading are altered in Cx43 deficient mice; and whether Cx43 is required for the effects of mechanical stimulation in osteoblasts and osteocytes in vitro. We expect that this work will provide opportunities to improve the treatment of diseases with increased bone fragility. PUBLIC HEALTH RELEVANCE: These studies will advance our understanding of the role of Cx43 in the response of the skeleton to pharmacotherapeutic, hormonal and mechanical stimuli. We expect that this work will provide opportunities to improve the treatment of diseases with increased bone fragility.

描述（由申请人提供）：连接蛋白（CX）是一个对细胞到细胞通信以及细胞与环境的通信所必需的蛋白质家族。 CX43是骨细胞中表达的最丰富的连接素。通过演示成骨细胞功能障碍和CX43无效小鼠胚胎中的成骨细胞功能障碍和延迟骨化，CX43表达在骨骼中的重要性。然而，CX43，特别是在无脑细胞膜中表达的CX43半通道的作用，远非完全理解。在导致该应用的研究中，证明双膦酸盐除了停止破骨细胞介导的吸收外，至少部分通过促进成骨细胞和骨细胞的生存力来保留骨强度，并且这种生存效应需要CX43表达。因此，双膦酸盐对凋亡的抑制需要开放CX43半通道，激活细胞外信号调节激酶（ERKS）以及激酶外的核外保持，由于它们与脚手架蛋白的相互作用（-artrestin。在CX43中缺乏的小鼠中，对激素的合成代谢反应也可能与机械刺激的机械转移有关，因此，机械刺激会增加CX43的cx43表达。由药理学，激素和机械刺激激活的成骨细胞和骨细胞的关键成分，通过其参与半通道或间隙连接或其脚手架特性，将通过内外和In Vivo的组合来测试。 AIM 1中的研究将检查CX43/（ - 使用双膦酸酯类似物对双膦酸盐作用在骨骼上作用的cx43/ERK途径有选择性地激活这一途径；它们将描述CX43，Erks和-arret蛋白在ERK和-Artection erk the Nortive and noctiation noctiation noctiation noctiation nosect and Intive nosectiation consect and cons and cons of noctiation cons and cos and cons of noctiation的机制。 CX43通过研究对CX43中缺乏的PTH给予小鼠的抗凋亡效应，这是由于PTH无法通过cx43 Hemichnels在VITRO IN in viviv in in in in in in in in in viviv中的作用，这是PTH无法防止成骨细胞骨的作用。在CX43缺陷的小鼠中，对机械负荷的反应发生了变化，以及在成骨细胞中机械刺激的影响和骨细胞在体外是否需要cx43。公共卫生相关性：这些研究将提高我们对CX43在骨架对药物治疗，荷尔蒙和机械刺激反应中的作用的理解。我们预计这项工作将为改善骨骼脆弱性增加的疾病治疗提供机会。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of connexins and pannexins during ontogeny, regeneration, and pathologies of bone.

DOI：
10.1186/s12860-016-0088-6
发表时间：
2016-05-24
期刊：
BMC cell biology
影响因子：
0
作者：
Plotkin LI;Laird DW;Amedee J
通讯作者：
Amedee J

Removing or truncating connexin 43 in murine osteocytes alters cortical geometry, nanoscale morphology, and tissue mechanics in the tibia.

DOI：
10.1016/j.bone.2016.04.021
发表时间：
2016-07
期刊：
Bone
影响因子：
4.1
作者：
Hammond MA;Berman AG;Pacheco-Costa R;Davis HM;Plotkin LI;Wallace JM
通讯作者：
Wallace JM

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging.

DOI：
10.1111/acel.12586
发表时间：
2017-06
期刊：
Aging cell
影响因子：
7.8
作者：
Davis HM;Pacheco-Costa R;Atkinson EG;Brun LR;Gortazar AR;Harris J;Hiasa M;Bolarinwa SA;Yoneda T;Ivan M;Bruzzaniti A;Bellido T;Plotkin LI
通讯作者：
Plotkin LI

In vitro and in vivo studies using non-traditional bisphosphonates.