Differential influence on bone remodeling by regulators of Wnt-dependent signal transduction

由于在骨质疏松症和骨质疏松症个体中分别发现了LRP 5基因的激活和失活突变，Wnt信号传导被认为是骨形成成骨细胞中的主要调控途径。 事实上，Lrp 5已被描述为Wnt家族配体的共受体和Wnt信号传导的内源性拮抗剂的分子靶标。 考虑到这些发现在骨骼疾病的骨合成代谢治疗方面的潜在相关性，基础科学的主要目标是了解Lrp 5在细胞表面的复杂相互作用，从而在分子水平上调节成骨细胞中的细胞内事件。 这是特别真实的问题，哪些特定的配体，受体和拮抗剂的Wnt信号是相关的骨形成，因为这些分子可以替代地被用作分子靶点的骨合成代谢therapy.Based我们自己的初步工作在这方面，我们得出了三个重要的结论：1）Wnt受体Fzd 9是骨形成的正调控因子。 2)跨膜蛋白Krm 2作为Wnt拮抗剂Dkk 1的受体发挥作用，是骨形成的负调节因子，另外激活破骨细胞生成。 3)虽然Krm 2抑制β-连环蛋白依赖性Wnt信号传导，但Fzd 9缺陷仅影响所谓的非经典Wnt信号传导途径。 为了进一步研究这些潜在的相关差异，该项目旨在产生用于组织学和分子分析的转基因小鼠模型，从而解决至少三个问题：1）Fzd 9是Lrp 5的生理相关相互作用伴侣吗？ 2)Krm 2的哪些分子效应是通过与Lrp 5的相互作用介导的？ 3)Sost的突变失活导致骨质疏松症，其作用是否由Wnt信号拮抗介导？

Since the discovery of activating and inactivating mutations of the gene LRP5 in individuals with osteosclerosis and osteoporosis, respectively, Wnt signaling is considered a major regulatory pathway in bone-forming osteoblasts. Indeed, Lrp5 has been described as a co-receptor for ligands of the Wnt family and as a molecular target for endogenous antagonists of Wnt signaling. Given the potential relevance of these findings in terms of an osteoanabolic treatment of skeletal disorders, it is a major goal of basic science to understand the complex interactions of Lrp5 at the cell surface and the thereby regulated intracellular events in osteoblasts at the molecular level. This is particularly true for the question, which specific ligands, receptors and antagonists of Wnt signaling are relevant for bone formation, since these molecules could alternatively be utilized as molecular targets for an osteoanabolic therapy.Based on our own preliminary work in this context we came to three important conclusions: 1) The Wnt receptor Fzd9 is a positive regulator of bone formation. 2) The transmembrane protein Krm2, which functions as a receptor of the Wnt antagonist Dkk1, is a negative regulator of bone formation that additionally activates osteoclastogenesis. 3) While Krm2 inhibits ß-catenin-dependent Wnt signaling, Fzd9-deficiency only affects so-called non-canonical Wnt signaling pathways. To further study these potentially relevant discrepancies, this project aims at the generation of genetically modified mouse models for histological and molecular analyses, thereby addressing at least three questions: 1) Is Fzd9 a physiologically relevant interaction partner of Lrp5? 2) Which molecular effects of Krm2 are mediated by an interaction with Lrp5? 3) Is the action of Sost, whose mutational inactivation causes osteosclerosis, mediated by Wnt signaling antagonism?