Analyzing the Role of Wnt Signaling in Bone Development

分析 Wnt 信号转导在骨骼发育中的作用

• 批准号: 8114152
• 负责人: Bart O Williams
• 金额: $ 35.56万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-10 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114152
• 关键词: Ablation; Address; Affect; Age-Months; Alleles; Bone Density; Bone Development; Bone Growth; Calvaria; Cessation of life; Chondrogenesis; Cytosol; Defect; Deposition; Development; Embryo; Genes; Human; In Vitro; Knock-out; Lead; Ligands; Limb structure; Measures; Mesenchyme; Mus; Mutate; Mutation; Osteoblasts; Osteocalcin; Osteoclasts; Osteoporosis; Phenotype; Play; Point Mutation; Proteins; Public Health; Regulation; Research Personnel; Role; Severities; Signal Pathway; Signal Transduction; Staging; Syndrome; Translating; Work; base; bone mass; insight; interest; mouse model; novel; novel strategies; osteoblast differentiation; osteochondral tissue; osteoclastogenesis; progenitor; programs; receptor

DESCRIPTION (provided by applicant): Osteoporosis pseudoglioma (OPPG), a human syndrome characterized by extremely low bone density, is caused by a deficiency in the Wnt co-receptor LRP5. Point mutations in this same receptor cause high bone mass by encoding for proteins with inappropriate signaling activity. The highly related LRP6 protein also influences bone mass. Given the intense interest in translating these findings into therapies to treat low bone mass, there is a critical need to understand how LRP5 and LRP6 protein control bone growth. Both LRP5 and LRP6 can transduce signals from Wnt ligands resulting in stabilization of (-catenin in the cytosol. To assess whether altered regulation of (-catenin underlies the phenotypes in humans an mice carrying mutated LRP5 and LRP6 genes, we and others have created mouse models in which the (-catenin gene was deleted at specific stages of osteoblast differentiation. We used osteocalcin-cre (OC-cre) to delete (-catenin in differentiated osteoblasts. OC-cre;(-cateninflox/flox mice die by one month of age, have elevated numbers of osteoclasts, and display severely low bone mass. Ablation of (-catenin in osteochondral precursors by Dermo1-cre blocks osteoblast differentiation and enhances chondrogenesis. In both cases, the phenotype of (-catenin ablation is much more severe than that of a global Lrp5 knockout. One explanation for difference in phenotypic severity between loss of p-catenin and deletion of Lrp5 is that Lrp6 can also regulate p-catenin in osteoblasts. In this proposal we examine the roles of Lrp6 and Lrp5 in early (commitment) and late stages of osteoblast differentiation. We predict that ablation of either Lrp5 or Lrp6 will have unique consequences at these stages, and that loss of both genes will cause more severe phenotypes. Relevant to Public Health: Addressing these questions has overarching implications: Figuring out how these receptors work will help to identify and validate novel targets and develop novel strategies for how to treat low bone mass as well as provide important insights into how the Wnt signaling pathway controls bone development.

描述（由申请人提供）：骨质疏松性假胶质瘤（OPPG）是一种以极低骨密度为特征的人类综合征，由Wnt辅助受体LRP 5缺乏引起。同一受体中的点突变通过编码具有不适当信号活性的蛋白质而导致高骨量。高度相关的LRP 6蛋白也影响骨量。鉴于将这些发现转化为治疗低骨量的疗法的强烈兴趣，迫切需要了解LRP 5和LRP 6蛋白如何控制骨生长。LRP 5和LRP 6都可以阻断来自Wnt配体的信号，导致胞质溶胶中β-连环蛋白的稳定。为了评估β-catenin调节的改变是否是携带突变LRP 5和LRP 6基因的人类和小鼠表型的基础，我们和其他人建立了小鼠模型，其中β-catenin基因在成骨细胞分化的特定阶段被删除。我们使用骨钙素-cre（OC-cre）来删除分化成骨细胞中的β-连环蛋白。OC-cre; β-cateninflox/flox小鼠在一个月大时死亡，具有升高的破骨细胞数量，并显示出严重的低骨量。通过Dermo 1-cre去除骨软骨前体中的β-连环蛋白阻断成骨细胞分化并增强软骨形成。在这两种情况下，β-连环蛋白消融的表型比整体Lrp 5敲除的表型严重得多。β-连环蛋白缺失和Lrp 5缺失之间表型严重性差异的一种解释是Lrp 6也可以调节成骨细胞中的β-连环蛋白。在这个建议中，我们研究Lrp 6和Lrp 5在成骨细胞分化的早期（承诺）和晚期阶段的作用。我们预测，Lrp 5或Lrp 6的消融将在这些阶段产生独特的后果，这两个基因的丢失将导致更严重的表型。与公共卫生有关：解决这些问题具有至关重要的意义：弄清楚这些受体如何工作将有助于识别和验证新的靶点，并为如何治疗低骨量开发新的策略，以及为Wnt信号通路如何控制骨发育提供重要的见解。