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: 10257699
• 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/10257699
• 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质流失， 严重的亚病变性骨质疏松症和脆性骨折增加。目前，没有广泛接受或 已被证实可用于治疗SCI卧床患者的骨质疏松症。抗骨吸收药物在治疗骨质疏松症中的疗效 对急性脊髓损伤患者的治疗受到质疑且无效。因此，迫切需要 开发新的治疗策略，以防止持续SCI后的骨丢失和提高骨质量。 这项建议的主要目的是确定最近发现的肌肉因子或 肌因子β-氨基异丁酸（BAIBA）减少慢性SCI后骨丢失。BAIBA一直是 显示出有效的成骨特性，并防止尾部悬吊小鼠的骨丢失， 减少骨质流失此外，BAIBA通过抑制， 骨细胞，氧化应激和改善线粒体功能。重要的是，我们的初步发现 表明来自SCI小鼠骨骼的骨细胞表现出受损的线粒体功能和增加的 氧化应激因此，我们建议检验假设，BAIBA政府将恢复 骨细胞功能，从而减少慢性SCI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的BAIBA恢复骨矿物质密度（BMD）， 慢性脊髓损伤后小鼠脑组织结构的变化。将BAIBA施用给20周龄C57 BL/6 J野生型雄性， 0、50、100或500 mg/kg/天剂量组雌性假手术或SCI小鼠饮用水。治疗将在35天后开始 SCI，并将持续35天，然后处死动物。终点分析将包括测量 双能X线骨密度仪（DXA）扫描和骨结构和微结构， 显微计算机断层扫描（Micro-CT）。骨转换标志物及影响因素的生化分析 还将使用特异性ELISA对收集的血清和骨髓（BM）上清液进行检测。 从机制上讲，将在BM上清液中评价BAIBA处理对氧化应激的影响， 骨细胞富集的骨提取物的SCI和对照小鼠使用特定的氧化应激试验。该项目 预期确定BAIBA的最佳治疗剂量，该剂量将减弱 固定在SCI动物的骨骼上。这个应用程序有可能发现一个新的 治疗策略，可能克服严重骨质疏松症的挑战，退伍军人与脊髓损伤，特别是 受伤多年后。我们提出以下具体目标： 目的：探讨白巴对慢性脊髓损伤后骨骼完整性的恢复作用。