Bone Abnormalities & Healing Defect in Muscular Dystrophy

骨骼异常

基本信息

批准号：
9263882
负责人：
Johnny Huard
金额：
$ 33.88万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-06 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263882
关键词：
6 year old Affect Age Aging Animal Model Animals Applications Grants Biomimetics Birth Blood Circulation Cardiomyopathies Cell Compartmentation Cell physiology Cells Cessation of life Congenital musculoskeletal anomalies Data Defect Deformity Disease Disease Progression Duchenne muscular dystrophy Dystrophin Exhibits FGF2 gene Fracture Functional disorder Goals Heart failure Hereditary Disease Heterotopic Ossification Histopathology Homeostasis Impaired wound healing Individual Infiltration Intervertebral disc structure Knock-out Knockout Mice Limb structure Longevity Mesenchymal Stem Cells Modeling Morphology Mus Muscle Muscle Weakness Muscular Atrophy Muscular Dystrophies Musculoskeletal Myocardium Myopathy Nature Osteopenia Pathology Patients Phenotype Play Proteins Quality of life Rejuvenation Reporting Respiratory Failure Role Series Skeletal Muscle Skeletal system Spinal Stem cells Teenagers Tissues Utrophin Wheelchairs Wild Type Mouse Work adult stem cell articular cartilage bone bone healing exhaustion experience experimental study fragility fracture healing improved improved functioning inhibitor/antagonist innovation juvenile animal mouse model muscle degeneration osteogenic premature prevent public health relevance regenerative repaired sarcopenia scoliosis skeletal skeletal abnormality skeletal muscle wasting stem cell niche theories

项目摘要

DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD) is a degenerative muscle disorder characterized by a lack of dystrophin expression that ultimately results in cardiac or respiratory failure. DMD patients also acquire osteopenia, fragility fracture, and scoliosis indicating that a deficiency in skeletal system homeostasis also occurs in DMD patients. It is speculated that these skeletal abnormalities are likely a secondary consequence to muscle loss (sarcopenia); however, it remains unclear if they could be due to a direct intrinsic skeletal defect. Recent evidence has emerged implicating adult stem cell dysfunction in the histopathogenesis of DMD. Muscle derived progenitor cells (MPCs) isolated from dystrophin/utrophin double knock-out (dKO) mice (a severe animal model of DMD) have been found to be defective in their proliferation and differentiation capacities. We, and others, have reported that these dKO mice exhibit a spectrum of degenerative changes in their bone, articular cartilage, and intervertebral discs and experience spinal deformities, heterotopic ossification, cardiomyopathy and a decreased lifespan, all of which support a premature musculoskeletal aging phenotype in this mouse model. A defect in bone healing was also observed in these mice; however, it is still unclear whether this defect is an intrinsic bone healing problem or associated with the secondary effects of sarcopenia (Aim 1). Preliminary evidence supports the existence of an adult stem cell defect in both MPCs and mesenchymal stem cells (MSCs) in these mice, supporting the theory that abnormal bone healing could be the consequence of an autonomous defect in the adult stem cell compartment. Thus the second aim of this project will be to further validate whether the MPCs and MSCs in these mice, analyzed at different ages, are defective in their proliferation and osteogenic differentiation capacities compared to MPCs and MSCs isolated from mdx and wild type (WT) mice. It has recently been shown that reducing fibroblast growth factor-2 (FGF2) activity prevents stem cell depletion/exhaustion; therefore, we also propose to determine whether FGF2 inhibitor-loaded biomimetic coacervate could rescue this autonomous adult stem cell defect and delay the onset of bone related histopathologies in dKO mice (Aim 2). Since there is also evidence that the stem cell niche may also negatively impact adult stem cell function, via a non-autonomous mechanism, we propose experiments to determine if the bone defect observed in dKO mice can be rescued through parabiotic pairing which will rejuvenate the dystrophic microenvironment by creating a shared circulation between a dKO and a young WT animal (Aim 3). We have preliminary data that supports the fact that circulating factors from young animals have a beneficial effect on the bone morphologies and healing capacity of dKO mice. In summary, this innovative grant application will: 1) determine whether the bone abnormalities and healing in dKO mice represent an intrinsic bone defect and 2) characterize whether the progressive bone histopathology observed in the dKO mice, is primarily driven by cell autonomous and/or non-autonomous mechanisms.

描述（由申请人提供）：Duchenne肌肉营养不良（DMD）是一种退化性肌肉疾病，其特征是缺乏肌营养不良蛋白表达，最终导致心脏或呼吸道衰竭。 DMD患者还获得骨质减少症，脆性骨折和脊柱侧弯，表明DMD患者还会出现骨骼系统稳态的缺乏。据推测，这些骨骼异常可能是肌肉损失的次要后果（肌肉减少症）。但是，目前尚不清楚它们是否可能是由于直接固有的骨骼缺陷。最近的证据已经出现了将成年干细胞功能障碍涉及DMD的组织病作用。肌肉衍生的祖细胞（MPC）从肌营养不良蛋白/乌托蛋白双敲除（DKO）小鼠（DMD的严重动物模型）中分离出来，其增殖和分化能力有缺陷。我们和其他人报告说，这些DKO小鼠的骨骼，关节软骨和椎间盘表现出了一系列的退化性变化，并且经历了脊柱畸形，异位骨化，心肌病和寿命下降，所有这些都支持了这种过早的肌肉骨骼衰减型在这种老鼠模型中。在这些小鼠中也观察到骨骼愈合的缺陷。但是，目前尚不清楚该缺陷是固有的骨愈合问题还是与肌肉减少症的次要作用有关（AIM 1）。初步证据支持在这些小鼠中MPC和间充质干细胞（MSC）中存在成年干细胞缺陷的存在，这支持了以下理论：异常骨骼愈合可能是成年干细胞室中自主缺陷的结果。因此，该项目的第二个目的是进一步验证这些小鼠的MPC和MSC在不同年龄分析的小鼠中是否有缺陷，与从MDX和MDX和野生型（WT）小鼠中分离出的MPC和MSC相比，它们的增殖和成骨分化能力是否有缺陷。最近已经显示，降低成纤维细胞生长因子2（FGF2）活性可防止干细胞耗竭/精疲力尽。因此，我们还建议确定FGF2抑制剂负载的仿生凝聚层是否可以挽救这种自主成年干细胞缺陷并延迟DKO小鼠中骨骼相关的组织病理学的发作（AIM 2）。 Since there is also evidence that the stem cell niche may also negatively impact adult stem cell function, via a non-autonomous mechanism, we propose experiments to determine if the bone defect observed in dKO mice can be rescued through parabiotic pairing which will rejuvenate the dystrophic microenvironment by creating a shared circulation between a dKO and a young WT animal (Aim 3).我们拥有初步数据，该数据支持这样一个事实，即来自幼小动物的循环因素对DKO小鼠的骨形态和愈合能力具有有益作用。总而言之，这种创新的赠款应用将：1）确定DKO小鼠中的骨异常和愈合是否代表了内在的骨缺损，2）2）表征在DKO小鼠中观察到的进行性骨组织病理学是否主要是由细胞自主和/或非自主机制驱动的。