Neurogenic bone loss after SCI: skeletal rehabilitation via Wnt and exercise interactions

SCI 后神经源性骨质流失：通过 Wnt 和运动相互作用进行骨骼康复

• 批准号: 10317142
• 负责人: ALEXANDER G ROBLING
• 金额: --
• 依托单位: RLR 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: 2021-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317142
• 关键词: Address; Adult; Affect; Antibodies; Antibody Therapy; Bone Tissue; Bone structure; Cardiovascular system; Combined Modality Therapy; Complication; Disease; Dose; Environment; Exercise; Fracture; Goals; Health; Homologous Gene; Injury; Kinetics; Lesion; Life; Maintenance; Mechanical Stimulation; Mechanics; Medical; Metabolism; Military Personnel; Motor; Motor Neurons; Mus; Muscle; Natural regeneration; Nature; Neurons; Osteopenia; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacotherapy; Phenotype; Physical Exercise; Population; Postmenopausal Osteoporosis; Property; Quality of life; Recovery; Rehabilitation therapy; Resistance; Risk Factors; Running; Senile Osteoporosis; Sensory; Skeletal Muscle; Skeleton; Speed; Spinal Cord Contusions; Spinal cord injury; Spinal cord injury patients; Stroke; Survival Rate; System; Therapeutic; Therapeutic Effect; Time; Tissues; Veterans; Visceral; WNT Signaling Pathway; Walking; Withdrawal; axon regeneration; base; behavioral outcome; bisphosphonate; bone; bone loss; bone mass; bone strength; cardiovascular disorder risk; density; design; efficacy testing; exercise rehabilitation; experimental study; fracture risk; functional outcomes; functional restoration; high risk; improved; long-term rehabilitation; mechanical load; mechanotransduction; member; military veteran; motor function improvement; mouse model; muscle regeneration; myogenesis; neurological rehabilitation; neuromuscular; neuromuscular rehabilitation; neutralizing antibody; novel; novel therapeutic intervention; optimal treatments; preservation; rehabilitation strategy; repair strategy; response; restoration; skeletal; skeletal injury; spinal cord repair; synergism; treadmill; wasting

The purpose of this application is to identify a long-term rehabilitative solution to skeletal fragility associated with spinal cord injury (SCI). SCI is one of the most debilitating medical conditions among the veteran population. Neurogenic osteopenia is a major complicating factor for SCI rehabilitation efforts, and there is currently a paucity of options for treating bone wasting associated with SCI. Thus, an urgent need exists to develop new rehabilitative strategies for preserving and/or restoring bone lost to SCI. This is particularly true given that significant advances are being made in neuromuscular rehabilitation (e.g., harnessing motoneuron plasticity and sprouting/regeneration mechanisms) for functional restoration; all of those efforts are in jeopardy if they are not accompanied by restoration of bone structure and strength, as fractures can nullify progress made in neurological rehabilitation. Although neurogenic bone loss is a different disease than standard postmenopausal osteoporosis (PMO) or senile osteoporosis, there are no approved therapies that specifically target the sequelae of SCI-induced bone loss. The closest drug option for SCI-induced bone loss is the sclerostin neutralizing antibody Romosozumab (“Romo”), due to its potent anabolic action and efficacy in mouse models of SCI. However, Romo received a black box warning from the FDA cautioning its use in patients at higher risk for cardiovascular disease and stroke, two risk factors that are significantly elevated in SCI patients. Therefore, while the bone-building effects of Romo are beneficial in SCI, its use at full strength is not suitable for SCI patients. We have found a combination therapy (sclerostin and Dkk1 neutralization) that reduces the sclerostin antibody dose by 83% (and total drug dose by 75%) yet still maintains all of the osteoanabolic action of full strength sclerostin antibody. Our overall goal is to is capitalize on the interaction between a very specific and novel osteoanabolic therapy (identified in our lab), and the powerful, lasting effects of mechanical stimulation (exercise), to define a rehabilitative strategy for neurogenic bone loss that will have lasting effects beyond the short-lived windows of most pharmaceutical options. Our approach takes into consideration the risk factors associated with SCI (e.g., elevated cardiovascular complications and stroke) and the beneficial effects of exercise to both the skeleton and to motor function to design a more tailored and focused approach to skeletal rehabilitation after SCI. In the first aim, we will determine whether an optimized ratio of sclerostin/Dkk1 antibody treatment can restore skeletal density, size, and strength after neurogenic bone loss from SCI. In the second aim, we will determine whether optimized sclerostin/Dkk1 antibody treatment can sensitize bone to the effects of mechanical exercise after SCI, producing a more robust and fracture-resistant skeleton. In the third aim, we will determine whether continued mechanical stimulation can maintain the beneficial skeletal effects of discontinued sclerostin/Dkk1 antibody treatment, ultimately providing a long-term, non-pharmacologic solution to skeletal maintenance after SCI. We will simultaneously assess motoneuron and skeletal muscle recovery, and functional/behavioral outcomes to evaluate the effect of the therapy on neuronal and muscle recovery. As (1) the activation of Wnt signaling and (2) exercise are both therapeutic for axonal regeneration, myogenesis, and skeletal health, the approach we propose is likely to have multi-systems benefit in SCI patients.

本应用的目的是确定与骨骼脆弱性相关的长期康复解决方案 脊髓损伤（SCI）。 SCI是老兵中最令人衰弱的医疗状况之一 人口。神经源性骨质减少症是SCI康复工作的主要复杂因素，并且有 目前，治疗与SCI相关的骨骼浪费的选择很少。那是迫切需要的 制定新的康复策略来保存和/或恢复对SCI失去的骨骼。这尤其正确 鉴于神经肌肉康复正在取得重大进展（例如，利用Motoneuron 可塑性和发芽/再生机制）功能恢复；所有这些努力都处于危险之中 如果它们不伴有骨骼结构和强度的恢复，因为裂缝会使进展无效 在神经康复中进行。尽管神经源性骨质流失与标准不同 绝经后骨质疏松症（PMO）或老年骨质疏松症，没有专门的批准疗法 靶向SCI诱导的骨质流失的后遗症。 Sci引起的骨质流失的最接近药物选择是 硬化蛋白中和抗体romosozumab（“ romo”），由于其有效的合成代谢作用和效率 SCI的鼠标模型。但是，罗莫收到了FDA的黑匣子警告，警告其在 患有心血管疾病和中风风险较高的患者，两个危险因素显着升高 SCI患者。因此，尽管Romo的骨建造效应在SCI中是有益的，但其全强度的使用是 不适合SCI患者。我们发现了一种联合疗法（硬化蛋白和DKK1中和） 将硬化蛋白抗体剂量降低了83％（总药剂量），但仍保持所有 全势硬化蛋白抗体的骨代谢作用。我们的总体目标是利用互动 在非常具体和新颖的骨代谢疗法（在我们的实验室中确定）和强大的，持久的效果之间 机械刺激（锻炼），以定义神经源性骨质流失的康复策略 持久的效果超出了大多数药物选择的短暂窗户。我们的方法采取了 考虑与SCI相关的危险因素（例如，心血管并发症和中风升高）和 运动对骨骼和运动功能的有益影响，以设计更量身定制的和 SCI后，重点进行骨骼康复的方法。在第一个目标中，我们将确定是否优化 硬化蛋白/DKK1抗体治疗的比率可以恢复神经源后骨骼密度，大小和强度 科幻骨质流失。在第二个目标中，我们将确定是否优化了硬化蛋白/DKK1抗体 治疗可以感知骨骼对SCI后的机械锻炼的影响，从而产生更健壮的和 抗断裂的骨骼。在第三个目标中，我们将确定持续的机械刺激是否可以 保持停用的硬化蛋白/DKK1抗体治疗的有益骨骼效应，最终提供 SCI后的长期，非药物解决方案。我们将简单地评估 运动神经元和骨骼肌恢复，以及功能/行为结果，以评估 关于神经元和肌肉恢复的治疗。 AS（1）Wnt信号的激活和（2）练习都是 轴突再生，肌发生和骨骼健康的治疗方法，我们提出的方法可能是 具有多系统受益于SCI患者。