Etiology of musculoskeletal maladies in NF1

项目总结/摘要 患有神经纤维瘤病1型（NF1）的儿童易患癌症，但也可能出现 胫骨单侧弯曲，通常会导致骨折。不像强壮的骨头 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 外科手术，通常是截肢。研究的重点是确定这种情况的原因 难治性骨愈合显示，骨髓间充质祖细胞中的Nf1缺乏使骨愈合变钝， 它们的成骨潜力并触发慢性和不受控制的RAS/ERK信号传导，尽管 阻断这一途径未能挽救骨祖细胞分化， 缺乏Nf1的小鼠的愈合是骨祖细胞。现在已经很清楚， 通路和代偿机制参与了Nf1的异常分化， 零骨祖细胞，并针对他们，以促进骨愈合的儿童与NF1将 非常有挑战性。这项建议偏离了这一战略，这要归功于对以下问题的观察： Nf1缺失的骨祖细胞的早期衰老，这应该使它们对"衰老清除剂"敏感。 毒品因此，我们的假设是，消除Nf1-null骨祖细胞-而不是纠正 他们的多重缺陷-与senolytics将促进骨愈合的儿童与NF1 假关节我们建议确定Nf1缺失的衰老骨祖细胞的清除， 在遗传上或基因上，改善了缺乏Nf1的小鼠的不良愈合潜力， 骨祖细胞，以及是否衰老相关的分泌表型（SASP）从 这些细胞改变有助于骨修复的谱系的行为。第二个大前提 这项工作的一个重要方面是观察到成年骨祖细胞中选择性缺乏Nf1的小鼠 失去肌肉。这一发现和其他体外和体内结果使我们挑战了 目前对肌肉内在缺陷的看法，并解决骨源性缺陷的假设， 来自Nf1缺失型骨祖细胞的因子导致在儿童中观察到的肌无力 与NF1，这也可以减轻清除NF1-空骨祖细胞与 senolytics。总体而言，这项工作有可能改善NF 1的临床管理 假关节的策略，将清除缺陷的Nf1-null骨祖细胞 并减轻它们对其他有助于骨修复的细胞的抑制作用， 强健的骨再生从机制上讲，这项研究可能支持Nf1-null 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阻止潜在的恶性转化， 骨骼修复和肌肉功能。

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.