Etiology of musculoskeletal maladies in NF1

NF1 肌肉骨骼疾病的病因学

• 批准号: 10207824
• 负责人: Florent Elefteriou
• 金额: $ 35.2万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207824
• 关键词: Address; Adult; Affect; Alkaline Phosphatase; Amputation; Behavior; Bone Regeneration; Bystander Effect; Cancer Etiology; Cell Differentiation process; Cell Lineage; Cells; Child; Chondrocytes; Chronic; Clinical Management; Data Set; Defect; Diphosphates; Disease; Etiology; Exhibits; Exposure to; Financial compensation; Fracture; Genetic; Homeostasis; Implant; In Vitro; Induced Mutation; Leg; Malignant - descriptor; Malignant Neoplasms; Mesenchymal; Mesenchymal Stem Cells; Modeling; Mus; Muscle; Muscle Cells; Muscle Weakness; Muscle function; Muscular Atrophy; Musculoskeletal; Mutate; Mutation; Myoblasts; NF1 gene; Natural regeneration; Neurofibromatosis 1; Orthopedics; Osteoblasts; Osteoclasts; Osteogenesis; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic calcification; Population; Predisposition; Preventive treatment; Process; Property; Pseudarthrosis; Quality of life; RNA; Refractory; Repeat Surgery; Replacement Therapy; Reporting; Research; Series; Signal Pathway; Signal Transduction; Skeletal system; Skeleton; Somatic Mutation; Therapeutic; Tissues; Work; base; bone; bone cell; bone fragility; bone healing; bone mass; cell suicide; clinically relevant; cost; healing; improved; in vivo; loss of function; macrophage; mechanical properties; mouse model; muscle form; muscular structure; muscular system; osteogenic; osteoprogenitor cell; paracrine; prevent; reduced muscle mass; repair function; senescence; targeted treatment; therapeutic target; tibia

Project Summary/Abstract Children with Neurofibromatosis Type 1 (NF1) are predisposed to cancer but can also present with unilateral bowing of the tibia that often progresses to fracture. Unlike the robust bone healing of most children, bone healing in these patients fails, leading to invasive and repeated surgeries, and often amputation of the leg. Research focused on identifying the cause of this refractory bone healing revealed that Nf1 deficiency in bone mesenchymal progenitors blunts their osteogenic potential and triggers chronic and uncontrolled RAS/ERK signaling, although blocking this pathway failed to rescue osteoprogenitor differentiation and the delayed bone healing of mice lacking Nf1 is osteoprogenitors. It has now become clear that multiple signaling pathways and compensatory mechanisms are involved in the abnormal differentiation of Nf1- null osteoprogenitors, and that targeting them to promote bone union in children with NF1 will be very challenging. This proposal steers away from this strategy, thanks to the observation of early senescence in Nf1-null osteoprogenitors, which should make them sensitive to “senolytic” drugs. Our hypothesis is thus that eliminating Nf1-null osteoprogenitors - rather than correcting their multiple defects – with senolytics will promote bone union in children with NF1 pseudarthrosis. We propose to determine if clearance of Nf1-null senescent osteoprogenitors, genetically or pharmacologically, improves the poor healing potential of mice lacking Nf1 in osteoprogenitors, and whether the senescence associated secretory phenotype (SASP) from these cells alters the behavior of lineages contributing to bone repair. A second major premise of this work is the observation that mice deficient for Nf1 selectively in adult osteoprogenitors lose muscle mass. This finding and other in vitro and in vivo results led us to challenge the current view of a muscle-intrinsic defect and to address the hypothesis that bone-derived factor(s) from Nf1-null osteoprogenitors contribute to the muscle weakness observed in children with NF1, which could also be alleviated by the clearance of Nf1-null osteoprogenitors with senolytics. Overall, this work has the potential to improve the clinical management of NF1 pseudarthrosis with a strategy that will pharmacologically clear faulty Nf1-null osteoprogenitors and relieve their inhibitory influence on other cells contributing to bone repair, thus restoring robust bone regeneration. Mechanistically, this study may support senescence in Nf1-null osteoprogenitors as a mechanism to prevent the spread of RAS-induced mutational damage and preclude potential malignant transformation at the cost of a deleterious bystander effect on bone repair and muscle function.

项目概要/摘要 患有 1 型神经纤维瘤病 (NF1) 的儿童容易患癌症，但也可能出现癌症 胫骨单侧弯曲，常常发展为骨折。与坚固的骨头不同 大多数儿童的愈合，这些患者的骨愈合失败，导致侵入性和反复 手术，通常是腿部截肢。研究的重点是确定造成这种情况的原因 难治性骨愈合揭示骨间充质祖细胞中的 Nf1 缺乏会减弱 它们的成骨潜力并触发慢性且不受控制的 RAS/ERK 信号传导，尽管 阻断该途径无法挽救骨祖细胞分化和骨延迟 缺乏 Nf1 的小鼠的愈合作用是骨祖细胞。现在已经清楚的是，多重信号 Nf1-的异常分化涉及途径和代偿机制 无效的骨祖细胞，并且针对它们来促进 NF1 儿童的骨愈合将是 非常具有挑战性。由于观察到，该提案偏离了这一策略 Nf1 缺失的骨祖细胞早衰，这应该使它们对“senolytic”敏感 药物。因此，我们的假设是消除 Nf1 缺失的骨祖细胞，而不是纠正 他们的多重缺陷——使用 senolytics 将促进 NF1 儿童的骨愈合 假关节。我们建议确定 Nf1 缺失的衰老骨祖细胞是否被清除， 通过遗传或药理学，改善缺乏 Nf1 的小鼠的不良愈合潜力 骨祖细胞，以及衰老相关分泌表型（SASP）是否来自 这些细胞改变了有助于骨修复的谱系的行为。第二个大前提 这项工作的重点是观察到成年骨祖细胞选择性缺乏 Nf1 的小鼠 失去肌肉质量。这一发现以及其他体外和体内结果使我们挑战 目前对肌肉固有缺陷的看法，并解决了骨源性缺陷的假设 Nf1 缺失骨祖细胞的因素导致儿童肌无力 NF1 的影响，也可以通过清除 Nf1 缺失的骨祖细胞来缓解 senolytics。总体而言，这项工作有可能改善 NF1 的临床管理 采用药物清除有缺陷的 Nf1 缺失骨祖细胞的策略治疗假关节 并减轻它们对其他有助于骨修复的细胞的抑制影响，从而恢复 强健的骨再生。从机制上讲，这项研究可能支持 Nf1 缺失中的衰老 骨祖细胞作为防止 RAS 诱导的突变损伤扩散的机制 并以有害的旁观者效应为代价来阻止潜在的恶性转化 骨骼修复和肌肉功能。