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.

患有慢性运动完全脊髓损伤（SCI）的退伍军人总是有骨损失和结果 严重的亚电骨质疏松症和脆弱性碎片增加。目前，没有被广泛接受或 对非肢体疏松症的骨质疏松症的经过验证治疗。反应剂在 对急性SCI的治疗方法已受到质疑和无效。结果，迫切需要 制定新的治疗策略，以防止骨质流失并在维持SCI后提高骨质质量。 该提案的主要目的是确定最近发现的肌肉因素的效率或 在慢性SCI后减少骨质损失的肌动物称为β-氨基异丁酸（Baiba）。 Baiba曾经 显示出暴露有效的成骨特性，并防止尾悬浮小鼠的骨质流失，这是一种模型 卸载骨质流失。此外，Baiba通过抑制，在 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 证明来自Sci小鼠骨骼的骨细胞暴露于线粒体功能并增加 氧化应激。根据，我们建议检验Baiba给药将恢复的假设 骨细胞功能因此减少了慢性科学后的骨质流失。在我们的研究目标中，我们将阐明 恢复骨矿物质密度（BMD）和 慢性科学后小鼠的结构。 Baiba将管理为20周大的C57BL/6J野生型男性，并且 雌性假小鼠在饮用水中以0、50、100或500 mg/kg/天/天。治疗将从35天开始 SCI并将持续35天，牺牲动物。端点分析将包括测量 双能X射线绝对测定法（DXA）扫描和骨结构以及微体系结构的BMD 微型层析成像扫描（Micro-CT）。骨化标记和因素的生化分析 还将使用特定ELISA对收集的血清和骨髓（BM）上清液进行。 从机械上讲，将评估Baiba治疗对BM上清液和氧化应激的影响 使用特定的氧化应激测定法，富含骨细胞的SCI和对照小鼠的骨提取物。该项目是 预计将确定Baiba的最佳治疗剂量，这将减轻 固定在Sci动物的骨骼上。该应用程序有可能发现新的 可以克服具有SCI的退伍军人的严重骨质疏松症的挑战的治疗策略 受伤多年。我们提出以下具体目标： 目的：确定Baiba对慢性SCI后恢复骨骼完整性的影响。