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EXPRESSION AND REGULATION OF GAP JUNCTION IN BONE CELLS

骨细胞间隙连接的表达和调控

基本信息

批准号：
6380801
负责人：
THOMAS H STEINBERG
金额：
$ 20.22万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-04-01 至 2003-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the Applicant's Abstract): Normal bone remodeling requires the coordinated activities of different bone cells, and is influenced by a variety of hormones and growth factors. Bone cells communicate via intercellular aqueous pores called gap junctions, and express three different gap junction proteins: connexin43 (Cx43), connexin45 (Cx45) and connexin46 (Cx46). Cx43 and Cx45 are found on the plasma membrane of osteoblasts, where they interact to form junctions with different molecular permeabilities. The relative abundance of Cx43 and Cx45 is a critical determinant of the expression of important bone proteins by these cells. In contrast, Cx46 has been found only in an intracellular pool in osteoblastic cells, suggesting that this gap junction protein is functional only in certain specialized circumstances. Bone cells also express P2U purinergic receptor, which mediate cell-cell communication by propagating calcium signaling among cells. Some of the hormones and growth factors that influence bone remodeling alter cell-cell communication. For instance, parathyroid hormone (PTH) and prostaglandin E2 (PGE2) affect bone protein production and also increase the expression and function of Cx43. This proposal seeks to test the hypothesis that intercellular communication is regulated spatially and temporally in bone cells in a manner that allows specific forms of intercellular communication. Using molecular and fluorescence imaging techniques, these studies seek to (1) define the expression of gap junction proteins and P2U receptors in vivo, by immunohistochemistry, and in vitro, in two physiologically relevant bone models, the MC3T3-E1 cell line and rat calvarial osteoblasts, under conditions where mineralization does and does not occur; (2) examine the function of gap junction proteins and P2U receptors under mineralizing and non-mineralizing conditions; and (3) examine the role of hormones, and other factors that influence bone turnover, on cell-cell communication in these models and explore the mechanisms by which observed effects occur. It is suggested (by the applicant) that these studies will define the ways in which physiologically relevant communication among bone cells is regulated, and suggest new approaches to the treatment of metabolic bone diseases such as osteoporosis.

描述（改编自申请人摘要）：正常骨重建需要不同骨细胞的协调活动，受多种激素和生长因子的影响。骨细胞通过称为间隙连接的细胞间水孔进行交流，表达三种不同的间隙连接蛋白：连接蛋白43（Cx43），连接蛋白45（Cx45）和连接蛋白46（Cx46）。 Cx43和Cx45位于成骨细胞的质膜，在那里它们相互作用，形成连接，不同的分子渗透性。 Cx43和Cx45的相对丰度是重要骨蛋白表达的关键决定因素，这些细胞。相反，Cx46仅在细胞内池中发现在成骨细胞中，这表明这种间隙连接蛋白是只有在特定的情况下才起作用。骨细胞也表达P2 U嘌呤能受体，其通过以下途径介导细胞间通讯：在细胞间传播钙信号。一些荷尔蒙和生长影响骨重塑的因素改变细胞-细胞通讯。为例如，甲状旁腺激素（PTH）和前列腺素E2（PGE 2）影响骨骼蛋白质的产生，并增加Cx43的表达和功能。这项提议试图验证细胞间通讯的假设，在骨细胞中以一种允许细胞间通讯的特殊形式。使用分子和荧光成像技术，这些研究试图（1）定义间隙连接蛋白和P2 U受体在体内的表达，免疫组织化学，并在体外，在两个生理相关的骨模型，MC 3 T3-E1细胞系和大鼠颅骨成骨细胞，在（2）在什么情况下发生和不发生矿化; 间隙连接蛋白和P2 U受体在矿化和非矿化条件;（3）检查激素的作用，以及其他影响骨转换的因素，在这些细胞中细胞间通讯模型，并探讨观察到的效果发生的机制。是（申请人）建议这些研究将确定调节骨细胞之间的生理相关通讯，并提出了治疗代谢性骨病的新方法，骨质疏松症