The efficacy of β-aminoisobutyric acid myokine to reduce bone loss after spinal cord injury

β-氨基异丁酸肌因子减少脊髓损伤后骨丢失的功效

• 批准号: 10400101
• 负责人: HESHAM A TAWFEEK
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400101
• 关键词: Acute; Aminoisobutyric Acids; Animal Model; Animals; Applications Grants; Architecture; Attenuated; Biochemical; Biological Assay; Biomechanics; Bone Density; Bone Growth; Bone Marrow; Bone structure; Cell physiology; Cellular Structures; Chronic; Clinical; Collaborations; Consumption; Data; Development; Devices; Disabled Persons; Distal; Dose; Dual-Energy X-Ray Absorptiometry; Environment; Enzyme-Linked Immunosorbent Assay; Exercise; Exhibits; Female; Femur; Fracture; Healthcare; Hindlimb Suspension; Immobilization; Impairment; Individual; Injury; Knee; Lesion; Lipid Peroxidation; Longevity; Lower Extremity; Measurement; Measures; Mediating; Medical center; Mitochondria; Modeling; Motor; Mus; Muscle; Musculoskeletal System; Names; Operative Surgical Procedures; Oral Administration; Osteocytes; Osteoporosis; Outcome; Oxidative Stress; Paralysed; Patients; Pharmaceutical Preparations; Physical activity; Pre-Clinical Model; Property; Quality of life; Randomized; Research Personnel; Resource Sharing; Risk; Scanning; Scientist; Site; Skeleton; Spinal Cord Contusions; Spinal cord injury; Stress; Structure; Tail; Testing; Therapeutic; Veterans; Walking; Wild Type Mouse; Work; authority; bone; bone cell; bone loss; bone mass; bone quality; bone strength; bone turnover; carbohydrate metabolism; drinking water; exoskeleton device; experience; experimental study; fracture risk; fragility fracture; high risk; improved; insight; lipid metabolism; male; member; microCT; mouse model; novel strategies; novel therapeutic intervention; novel therapeutics; osteogenic; powered exoskeleton; prevent; protective effect; skeletal; tibia; tomography

Veterans with chronic motor complete spinal cord injury (SCI) invariably have had bone loss and resultant severe sub-lesional osteoporosis and increased fragility fractures. Currently, there is no widely accepted or proven treatment for osteoporosis in non-ambulatory patients with SCI. The efficacy of anti-resorptive agents in the treatment of those with acute SCI has been questioned and ineffective. As a result, there is an urgent need to develop new therapeutic strategies to prevent bone loss and enhance bone quality after sustaining a SCI. The primary objective of this proposal is to determine the efficacy of a recently-discovered muscle factor or myokine named β-aminoisobutyric acid (BAIBA) on reducing bone loss after chronic SCI. BAIBA has been shown to exhibit potent osteogenic properties and to prevent bone loss in tail suspended mice, a model of unloading bone loss. Furthermore, BAIBA produced its favorable osteogenic properties by inhibiting, in osteocytes, oxidative stress and improving mitochondrial function. Importantly, our preliminary findings demonstrate that osteocytes from bones of SCI mice exhibit impaired mitochondrial function and increased oxidative stress. Accordingly, we propose to test the hypothesis that BAIBA administration will restore osteocyte function thus reducing bone loss after chronic SCI. In our study aim, we will elucidate the effects of oral administration of vehicle and different doses of BAIBA on restoring bone mineral density (BMD) and structure in mice after chronic SCI. BAIBA will be administered to 20 week old C57BL/6J wild type male and female sham or SCI mice in drinking water at 0, 50, 100, or 500 mg/kg/day. Treatment will start 35 days after SCI and will continue for 35 days when animals will be sacrificed. Endpoint analyses will include measurement of BMD by Dual energy x-ray absorptiometry (DXA) scanning and bone structure and microarchitecture by microcomputed tomography scanning (Micro-CT). Biochemical analysis of bone turnover markers and factors will also be performed on collected sera and bone marrow (BM) supernatants using specific ELISA. Mechanistically, the effects of BAIBA treatment on oxidative stress will be evaluated on BM supernatants and osteocyte-enriched bone extracts of SCI and control mice using specific oxidative stress assays. The project is expected to identify the optimal therapeutic dose of BAIBA that will attenuate the deleterious effects of immobilization on the skeleton of SCI animals. This application has the potential of discovering a new therapeutic strategy that may overcome the challenge of severe osteoporosis in Veterans with SCI specifically many years after injury. We propose the following specific aim: Aim: To determine the effects of BAIBA on restoring skeletal integrity after chronic SCI.

患有慢性运动性完全性脊髓损伤(SCI)的退伍军人总是有骨丢失和由此导致的 严重的亚皮质疏松症和增加的脆性骨折。目前，没有被广泛接受的或 非卧床脊髓损伤患者骨质疏松症的有效治疗。抗吸收药物的疗效观察 那些急性脊髓损伤患者的治疗一直受到质疑，而且效果不佳。因此，迫切需要 开发新的治疗策略，以防止脊髓损伤后的骨丢失和提高骨质量。 这项建议的主要目标是确定最近发现的肌肉因子或 一种名为β-氨基异丁酸(BAIBA)的肌细胞因子，可减少慢性脊髓损伤后的骨丢失。白坝一直是 显示出强大的成骨性能，并防止尾部悬吊小鼠的骨丢失，一个模型 减轻骨质流失。此外，BAIBA通过抑制BAIBA中的BAIBA，产生其良好的成骨特性。 骨细胞、氧化应激和改善线粒体功能。重要的是，我们的初步调查结果 证明脊髓损伤小鼠骨骼中的骨细胞表现出线粒体功能受损和增加 氧化应激。因此，我们建议检验BAIBA管理将恢复 骨细胞功能，从而减少慢性脊髓损伤后的骨丢失。在我们的研究目标中，我们将阐明 口服赋形剂和不同剂量BAIBA对小鼠骨密度和骨密度的影响 慢性脊髓损伤后小鼠的组织结构。20周龄C57BL/6J野生型雄性和 雌性假手术或脊髓损伤小鼠每天饮用0、50、100或500 mg/kg的水。治疗将在35天后开始 并将持续35天，届时动物将被处死。终点分析将包括测量 应用双能X线骨密度仪(DXA)扫描测定骨密度及骨结构和微结构 微型计算机断层扫描(Micro-CT)。骨转换标志物及其影响因素的生化分析 也将对收集的血清和骨髓(BM)上清液进行特异性酶联免疫吸附试验。 从机制上讲，BAIBA处理对氧化应激的影响将在骨髓上清液和 用特定氧化应激试验检测脊髓损伤小鼠和对照小鼠的富含骨细胞的骨提取物。该项目是 希望确定BAIBA的最佳治疗剂量，以减轻 脊髓损伤动物骨骼的固定。这个应用程序有可能发现一个新的 可克服退伍军人严重骨质疏松挑战的治疗策略 受伤很多年后。我们提出以下具体目标： 目的：探讨BAIBA对慢性脊髓损伤后骨骼完整性的恢复作用。