The LRP5 Pathway and Osteoblast Function In Osteogenesis Imperfecta

成骨不全症中的 LRP5 通路和成骨细胞功能

• 批准号: 10450080
• 负责人: CHRISTINA MARIE JACOBSEN
• 金额: $ 62.03万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450080
• 关键词: Adult; Agonist; Alleles; Anabolism; Antibodies; Binding; Bone Density; Bone Matrix; COL1A1 gene; COL1A2 gene; Cell Surface Receptors; Cells; Child; Clinical; Collagen; Collagen Gene; Collagen Type I; DNA Sequence Alteration; Data; Development; Fracture; Functional disorder; Genes; Genetic Diseases; Human; In Vitro; LDL-Receptor Related Protein 1; LDL-Receptor Related Proteins; Lead; LoxP-flanked allele; Medical; Missense Mutation; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Pathological fracture; Pathway interactions; Patient-Focused Outcomes; Patients; Population; Production; Property; Signal Pathway; Signal Transduction; Swelling; Testing; Type I Procollagen; WNT Signaling Pathway; Wild Type Mouse; Work; antagonist; bone; bone health; bone mass; bone strength; bone turnover; gain of function mutation; improved; improved functioning; in vivo; inhibitor; lipoprotein receptor related protein 5; mouse model; mutant; neutralizing antibody; new therapeutic target; novel strategies; offspring; prevent; protein transport; recruit; single-cell RNA sequencing; skeletal; small molecule; targeted treatment; trafficking; treatment effect

Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass that predisposes children and adults to skeletal fracture. Most patients with OI have a mutation in one of the two genes that encode type 1 collagen. Current medical therapies for patients with OI are limited, acting by preventing bone turnover to increase bone mass and do not decrease fracture rate in all patients. Our previous work has shown that enhancing bone anabolism via the low density lipoprotein receptor related-protein 5 (LRP5) signaling pathway, either through a genetic mutation that increases signaling or administration of an antibody that binds an inhibitor of the pathway, leads to significant increases in bone mass and bone strength in several mouse models of OI caused by dominant type 1 collagen mutations. In addition, we have shown that osteoblasts from mice with OI have ER swelling that improves with increased LRP5 signaling, suggesting that protein trafficking is improved. This is important as therapies (Sclerostin antibody) are available that increase LRP5 signaling and our data suggest they will be have dual beneficial effects in patients with OI, both increasing bone matrix production and improving osteoblast function. In the present application, we propose to utilize two different mouse models of dominant OI 1) To identify the molecular mechanisms by which an Lrp5 HBM mutation improves protein trafficking of type I collagen in dominant forms of OI, 2) To determine the effect of treatment with Sclerostin antibody on osteoblast development and function in OI and 3) To determine if increased LRP5 signaling is required during osteoblast development to improve osteoblast function in dominant forms of OI. The successful completion of these aims will allow for greater understanding of the mechanisms by which increased LRP5 signaling both increases collagen production and improves osteoblast function. Together the results will show that therapies targeting LRP5 signaling, unlike other currently available treatments, not only increase collagen production but also treat the specific osteoblast dysfunction seen in OI, which may lead to better outcomes for patients.

成骨不全症 (OI) 是一种遗传性疾病，其特征是骨量低，容易诱发 儿童和成人骨骼骨折。大多数成骨不全患者的两个基因之一都有突变， 编码 1 型胶原蛋白。目前针对成骨不全患者的药物疗法有限，只能通过预防骨 周转以增加骨量，但不会降低所有患者的骨折率。我们之前的工作已经表明 通过低密度脂蛋白受体相关蛋白 5 (LRP5) 信号传导增强骨合成代谢 途径，要么通过增加信号传导的基因突变，要么通过施用结合的抗体 该途径的抑制剂，导致一些小鼠的骨量和骨强度显着增加 由 1 型胶原显性突变引起的 OI 模型。此外，我们还发现，成骨细胞来自 患有 OI 的小鼠的 ER 肿胀随着 LRP5 信号传导的增加而改善，这表明蛋白质运输 得到改善。这一点很重要，因为可以使用增加 LRP5 信号传导和 我们的数据表明它们对成骨不全患者具有双重有益作用，既可以增加骨基质 生产和改善成骨细胞功能。在本申请中，我们建议使用两种不同的 显性 OI 小鼠模型 1) 确定 Lrp5 HBM 突变的分子机制 改善 OI 的主要形式中 I 型胶原蛋白的蛋白质运输，2) 确定 使用 Sclerostin 抗体治疗对成骨不全症中成骨细胞发育和功能的影响，以及 3) 确定是否 成骨细胞发育过程中需要增加 LRP5 信号传导以改善成骨细胞功能 成骨不全症的主要形式。这些目标的成功实现将使人们对 增加 LRP5 信号传导既增加胶原蛋白生成又改善成骨细胞的机制 功能。这些结果将表明，与目前可用的其他疗法不同，针对 LRP5 信号传导的疗法 治疗不仅可以增加胶原蛋白的产生，还可以治疗成骨不全症中出现的特定成骨细胞功能障碍， 这可能会给患者带来更好的结果。