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: 7317506
• 负责人: Bart O Williams
• 金额: $ 40.05万
• 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/7317506
• 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; Numbers; 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; insight; interest; mouse model; novel; novel strategies; 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)：骨质疏松症假性胶质瘤(OPPG)是一种以极低骨密度为特征的人类综合征，由Wnt共同受体LRP5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骨量增加。高度相关的LRP6蛋白也会影响骨量。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LRP5和LRP6蛋白是如何控制骨生长的。LRP5和LRP6都可以转导来自Wnt配体的信号，从而稳定胞浆中的(-catenin)。为了评估人类和携带突变LRP5和LRP6基因的小鼠的表型是否存在(-catenin的调节变化)，我们和其他人建立了小鼠模型，在成骨细胞分化的特定阶段，(-catenin基因被删除)。我们使用骨钙素-cre(OC-cre)在分化的成骨细胞中删除(-catenin)。Occre；(-cateninflox/flx小鼠在一个月龄前死亡，破骨细胞数量增加，骨量严重减少。用Dermo1-cre去除骨软骨前体细胞中的(-catenin)可阻断成骨细胞分化，促进软骨形成。在这两种情况下，(-catenin消融的表型比全局LRP5基因敲除的表型严重得多。P-catenin缺失和LRP5缺失的表型严重程度不同的一种解释是LRP6也可以调节成骨细胞中的p-catenin。在这项研究中，我们研究了LRP6和LRP5在成骨细胞分化的早期和晚期的作用。我们预测，LRP5或LRP6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。与公共健康相关：解决这些问题具有重要的意义：弄清楚这些受体是如何工作的，将有助于识别和验证新的靶点，开发如何治疗低骨量的新策略，并为Wnt信号通路如何控制骨骼发育提供重要的见解。