Bone Abnormalities & Healing Defect in Muscular Dystrophy

骨骼异常

• 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
• 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

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）：杜氏肌营养不良症（DMD）是一种退行性肌肉疾病，其特征是缺乏肌营养不良蛋白表达，最终导致心脏或呼吸衰竭。DMD患者还会出现骨质减少、脆性骨折和脊柱侧凸，这表明骨骼系统稳态缺陷也发生在DMD患者中。据推测，这些骨骼异常可能是肌肉损失（肌肉减少症）的继发性后果；然而，尚不清楚它们是否可能是由直接的内在因素引起的