Etiology of musculoskeletal maladies in NF1

项目摘要/摘要 患有1型神经纤维瘤病(NF1)的儿童易患癌症，但也可能 伴有胫骨单侧弯曲，常进展为骨折。与健壮的骨骼不同 大多数儿童愈合，这些患者的骨愈合失败，导致侵入性和反复性 手术，经常是截肢。研究的重点是找出造成这种情况的原因 难治性骨愈合显示骨髓间充质祖细胞中NF1缺乏使其钝化 它们的成骨能力并触发慢性和不受控制的RAS/ERK信号，尽管 阻断这一途径未能挽救成骨分化和延迟的骨 缺乏NF1的小鼠的愈合是成骨细胞。现在已经很清楚了，多个信号 NF1-1异常分化涉及多种途径和代偿机制 无效的骨祖细胞，并以它们为靶点促进NF1儿童的骨愈合将是 非常具有挑战性。这项提议偏离了这一战略，这要归功于对 NF1缺失的骨祖细胞的早期衰老，这应该使它们对“衰老”敏感 毒品。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--使用感觉剂将促进NF1儿童的骨愈合 假关节。我们建议确定NF1缺失的衰老成骨细胞是否被清除， 从遗传学或药理学角度，改善缺乏NF1的小鼠的愈合潜力 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。第二个主要前提 这项工作的一项工作是观察到缺乏NF1的小鼠选择性地在成年成骨祖细胞中 失去肌肉质量。这一发现以及其他体外和体内结果促使我们挑战 目前对肌肉固有缺陷的看法，并解决了骨来源的假说 来自NF1缺失的骨祖细胞的因子(S)导致儿童肌肉无力 使用NF1，这种情况也可以通过清除NF1缺失的成骨细胞来缓解 感光剂。总体而言，这项工作有可能改善NF1的临床管理 假性关节病，其策略将在药物上清除有缺陷的NF1缺失的骨祖细胞 并解除它们对其他有助于骨骼修复的细胞的抑制影响，从而恢复 强健的骨骼再生能力。从机制上讲，这项研究可能支持NF1的衰老-NULL 骨祖细胞作为防止RAS所致突变损伤扩散的机制 并以有害的旁观者效应为代价防止潜在的恶性转化 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.