Pathogenesis of LRP6 High Bone Mass

LRP6 高骨量的发病机制

• 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
• 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

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.

项目摘要 LRP 5编码低密度脂蛋白受体相关蛋白5（LRP 5）。当LRP 5与卷曲 受体连接在成骨细胞（OB）的表面，并结合Wnt家族的配体，典型的 Wnt/β-连环蛋白信号传导发生并增加骨形成。11个杂合子功能获得性错义 已知LRP 5内的突变阻止LRP 5抑制性配体sclerostin和dickkopf 1附着 LRP 5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 质量”（HBM）。LRP 6是LRP 5的同源共受体，并且类似地控制成骨细胞中的Wnt信号传导，然而 直到现在，LRP 6介导的信号传导增加的后果仍然未知。我们调查了两个 多代美国家庭表现出LRP 5 HBM的临床和常规实验室特征， 没有LRP 5缺陷，而是携带杂合LRP 6错义突变（c.602C>T，p.A201V或p.A201V）， c.553A>C，p.N185H）。在这两个家族中，LRP 6突变与显著的全身性骨质疏松共分离。 和骨质增生。7名LRP 6 HBM家族成员和10名LRP 5 HBM患者共有的临床特征 包括宽阔的下颚，腭隆凸，被骨头包裹的牙齿，据报道， 在水中漂浮。然而，我们的LRP 5和LRP 6家族之间存在显著的临床差异。DXA LRP 6 HBM与LRP 5 HBM的腰椎平均BMD Z评分略高， 仅在LRP 6 HBM家族中存在年龄差异。一些人报告说，成人上颌侧切牙缺失 在两个LRP 6 HBM家族中均发现有LRP 6 HBM成员，但在LRP 5 HBM中未发现。因此，我们发现了 LRP 6引起的牙-骨疾病类似于LRP 5 HBM，但有一些差异。我们想 阐明这些LRP 5和LRP 6 HBM突变在OB和破骨细胞（OC）中的作用机制， 因为最近的数据显示WNT信号传导在抑制OC发育和功能中是重要的。我们提出 为了从LRP 5和LRP 6 HBM患者来源的细胞（肾脏或肾脏）制备诱导多能干细胞（iPSC）， 来自尿或血液白细胞的细胞）。然后，我们将比较和对比OB的发展和功能， LRP 5和LRP 6患者来源的iPSC，沿着对照iPSC。我们还将评估OB中的Wnt信号传导， 这两种突变细胞类型来寻找疾病机制的细微差异。我们还将评估 LRP 5和LRP 6突变对OC发育和功能的影响，并启动Wnt 在两种突变细胞类型中的信号传导研究。我们的研究结果将有助于更好地理解WNT信号转导， 骨发育和周转，并帮助指导开发更好的治疗人类疾病， 高和低（即骨质疏松症）骨量。