Cadherin Mediated Cell-Cell Interactions in the Bone Microenvironment

骨重建缺陷是大多数代谢性骨病的病理生理基础， 包括绝经后和年龄依赖性骨质疏松症。在以前的工作中，我们发现 成骨细胞表达细胞粘附分子钙粘蛋白超家族的成员， 特别是钙粘蛋白-11（Cad 11）和N-钙粘蛋白（Ncad）。钙粘蛋白介导细胞-细胞粘附， 但它们也通过稳定细胞表面的β-连环蛋白而与Wnt信号通路交叉。 细胞-细胞粘附也是间隙连接和细胞间粘附组装的先决条件。 通信我们已经证明，无论是显性-负性的钙粘蛋白破坏， Ncad和/或Cad 11基因（Cdh 2和Cadh 11）的功能或隐性无效突变， 小鼠阻碍骨形成，导致低峰值骨量和骨质减少。我们还发现 钙粘蛋白缺乏会对Wnt/β-连环蛋白系统产生负面影响， 细胞间连接（粘附和间隙连接），体外。这个问题的核心假设是 项目是钙粘蛋白（Ncad和Cad 11）控制成骨分化， 调节骨髓微环境中的细胞-细胞相互作用，通过细胞-细胞 粘附、通信和信号。我们进一步假设Ncad和Cad 11具有 部分重叠，但在成骨细胞分化程序中的作用不同。实现这一 目的，我们建议确定，1）Cdh 2和Cdh 11在骨形成细胞中的相对作用， 在出生后骨骼的承诺和分化和增殖; 2）相互作用 钙粘蛋白（Ncad和Cad 11）和Wnt信号在成骨细胞分化中的作用， 功能和3）钙粘蛋白依赖的组织和细胞间连接的功能 （粘附和间隙连接）在成骨分化中的作用。我们将使用多种体外、离体 以及体内方法，基于我们开发的钙粘蛋白基因消融小鼠模型， 研究钙粘蛋白缺乏对骨发育、骨量和 骨祖细胞募集和分化。我们还将确定细胞和 钙粘蛋白缺陷小鼠骨量减少的分子基础。该提案涉及 在骨微环境中调节骨转换的基本机制。 了解钙粘蛋白在骨生物学中的作用对于全面了解骨组织中钙粘蛋白的表达是至关重要的。 控制骨骼发育和体内平衡的分子网络。

Defective bone remodeling is the pathophysiologic basis of most metabolic bone diseases, including postmenopausal and age-dependent osteoporosis. In previous work, we have found that osteoblasts express members of the cadherin superfamily of cell adhesion molecules, in particular cadherin-11 (Cad11) and N-cadherin (Ncad). Cadherins mediate cell-cell adhesion, but they also intersect the Wnt signaling pathway by stabilizing ¿-catenin on the cell surface. Cell-cell adhesion is also a pre-requisite for assembly of gap junctions and intercellular communication. We have demonstrated that either dominant-negative disruption of cadherin function or recessive null mutations of the Ncad and/or Cad11 genes (Cdh2 and Cadh11) in mice hinders bone formation, leading to low peak bone mass and osteopenia. We also find that cadherin deficiency negatively affects the Wnt/¿-catenin system and reduces the abundance of intercellular junctions (adherens and gap junctions), in vitro. The central hypothesis of this project is that cadherins (Ncad and Cad11) control osteogenic differentiation by modulating cell-cell interactions in the bone marrow microenvironment, via cell-cell adhesion, communication and signaling. We further hypothesize that Ncad and Cad11 have partially overlapping, yet distinct roles in the osteoblast differentiation program. To achieve this goal, we propose to determine, 1) the relative roles of Cdh2 and Cdh11 in bone forming cell commitment and differentiation and proliferation in the post-natal skeleton; 2) the interactions between cadherins (Ncad and Cad11) and Wnt signaling in osteoblast differentiation and function and 3) cadherin dependent organization and function of intercellular junctions (adherens and gap junctions) in osteogenic differentiation. We will use multiple in vitro, ex vivo and in vivo approaches, based on cadherin gene ablation mouse models we have developed, to study the consequences of cadherin deficiency on bone development, bone mass and osteoprogenitor cell recruitment and differentiation. We will also determine the cellular and molecular bases of the osteopenia of cadherin deficient mice. This proposal addresses fundamental mechanisms by which bone turnover is modulated in the bone microenvironment. Understanding the role of cadherins in bone biology is essential to gain a full picture of the molecular network by which bone development and homeostasis are controlled.