Pathogenesis of LRP6 High Bone Mass

LRP6 高骨量的发病机制

基本信息

批准号：
10445060
负责人：
STEVEN R MUMM
金额：
$ 17.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-06 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445060
关键词：
Actins Adult Affect Age American Amino Acids Binding Bone Development Cells Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases DNA Sequence Alteration Data Defect Development Diagnostic Disease Distal Dual-Energy X-Ray Absorptiometry Family Family member Finite Element Analysis Forearm Fracture Generations Genes Hereditary Multiple Exostoses Hip region structure Human Hyperostosis Impairment Incisor Individual Jaw LDL-Receptor Related Protein 1 Laboratories Lateral Leukocytes Ligands Lipoprotein Receptor Maxilla Mediating Missense Mutation Modeling Mutation Osteoblasts Osteoclasts Osteogenesis Osteoporosis Osteosclerosis Pathogenesis Pathway interactions Patients Phenotype Positioning Attribute Proteins Reporting Resistance Role Signal Transduction Surface Tooth structure Urine Vertebral column WNT Signaling Pathway Water age effect beta catenin bone bone cell bone mass bone turnover cell motility cell type gain of function girls human disease induced pluripotent stem cell kidney cell lipoprotein receptor related protein 5 long bone member mutant osteoclast progenitor prevent receptor skeletal disorder

项目摘要

Project Summary LRP5 encodes low-density lipoprotein receptor-related protein 5 (LRP5). When LRP5 with a Frizzled receptor join on the surface of an osteoblast (OB) and bind a member of the Wnt family of ligands, canonical Wnt/β-catenin signaling occurs and increases bone formation. Eleven heterozygous gain-of-function missense mutations within LRP5 are known to prevent the LRP5 inhibitory ligands sclerostin and dickkopf1 from attaching to LRP5's first β-propeller, and thereby explain the rare autosomal dominant (AD) skeletal disorder “high bone mass” (HBM). LRP6 is a cognate co-receptor of LRP5 and similarly controls Wnt signaling in osteoblasts, yet the consequences of increased LRP6-mediated signaling remained unknown, until now. We investigated two multi-generational American families manifesting the clinical and routine laboratory features of LRP5 HBM but without an LRP5 defect and instead carrying a heterozygous LRP6 missense mutation (c.602C>T, p.A201V or c.553A>C, p.N185H). In both families, the LRP6 mutation co-segregated with striking generalized osteosclerosis and hyperostosis. Clinical features shared by the seven LRP6 HBM family members and ten LRP5 HBM patients included a broad jaw, torus palatinus, teeth encased in bone and, reportedly, resistance to fracturing and inability to float in water. However, there were significant clinical differences between our LRP5 and LRP6 families. DXA mean BMD Z-scores in LRP6 HBM versus LRP5 HBM were somewhat higher at the lumbar spine, and increased with age only in the LRP6 HBM families. Absence of adult maxillary lateral incisors was reported by some members in both LRP6 HBM families, but was not noted in LRP5 HBM. Hence, we have discovered mutations of LRP6 that cause a dento-osseous disorder similar to LRP5 HBM, but with some differences. We want to elucidate the mechanism of action for these LRP5 and LRP6 HBM mutations in both OBs and osteoclasts (OCs), since recent data shows that WNT signaling is important in inhibiting OC development and function. We propose to make induced pluripotent stem cells (iPSCs) from LRP5 and LRP6 HBM patient-derived cells (either kidney cells from urine or blood leukocytes). We will then compare and contrast OB development and function using LRP5 and LRP6 patient-derived iPSCs, along with control iPSCs. We will also assess Wnt signaling in OBs, for both mutant cell types to look for subtle differences in the mechanism of disease. We will also assess the impact of LRP5 and LRP6 mutations on OC development and function using patient-derived iPSCs, and initiate Wnt signaling studies in both mutant cell types. Our findings will lead to a better understanding of WNT signaling in bone development and turnover, and help guide development of better treatments for human diseases of both high and low (i.e. osteoporosis) bone mass.

项目概要 LRP5 编码低密度脂蛋白受体相关蛋白 5 (LRP5)。受体连接在成骨细胞 (OB) 表面并结合 Wnt 配体家族的成员，经典 Wnt/β-连环蛋白信号传导发生并增加骨形成。 11 个杂合的功能获得性错义。已知 LRP5 内的突变会阻止 LRP5 抑制性配体 sclerostin 和 dickkopf1 的附着 LRP5的第一个β-螺旋桨，从而解释了罕见的常染色体显性（AD）骨骼疾病“高骨 Mass” (HBM) 是 LRP5 的同源共受体，并且类似地控制成骨细胞中的 Wnt 信号传导。到目前为止，我们研究了两个 LRP6 介导的信号传导增加的后果仍然未知。多代美国家庭表现出 LRP5 HBM 的临床和常规实验室特征，但没有 LRP5 缺陷，而是携带杂合 LRP6 错义突变（c.602C>T、p.A201V 或 c.553A>C，p.N185H）在两个家族中，LRP6 突变与显着的全身性骨硬化症共分离。七名 LRP6 HBM 家族成员和十名 LRP5 HBM 患者共有的临床特征。包括宽阔的下巴、腭环、包裹在骨头中的牙齿，据报道，它具有抗骨折和无能力的能力然而，我们的 LRP5 和 LRP6 家族之间存在显着的临床差异。 LRP6 HBM 与 LRP5 HBM 中的平均 BMD Z 分数在腰椎处稍高，并且增加一些人报告称，仅 LRP6 HBM 家族中没有成人上颌侧切牙。两个 LRP6 HBM 家族的成员，但在 LRP5 HBM 中未发现，因此，我们发现了突变。 LRP6 引起的牙骨疾病与 LRP5 HBM 类似，但有一些差异。阐明 OB 和破骨细胞 (OC) 中 LRP5 和 LRP6 HBM 突变的作用机制，因为最近的数据表明 WNT 信号传导对于抑制 OC 的发展和功能很重要。从 LRP5 和 LRP6 HBM 患者来源的细胞（肾或肾）制造诱导多能干细胞 (iPSC) 然后我们将使用 OB 的发育和功能进行比较和对比。 LRP5 和 LRP6 患者来源的 iPSC 以及对照 iPSC 还将评估 OB 中的 Wnt 信号传导。我们还将评估两种突变细胞类型在疾病机制中的细微差异。使用患者来源的 iPSC 分析 LRP5 和 LRP6 突变对 OC 发育和功能的影响，并启动 Wnt 我们对两种突变细胞类型的信号传导研究将有助于更好地理解 WNT 信号传导。骨骼发育和更新，并有助于指导开发更好的人类疾病治疗方法高和低（即骨质疏松症）骨量。