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.

此应用程序的目的是确定与骨骼脆性相关的长期康复解决方案 合并脊髓损伤(SCI)。脊髓损伤是退伍军人中最令人衰弱的疾病之一 人口。神经源性骨量减少是脊髓损伤康复努力的主要复杂因素， 目前，治疗与脊髓损伤相关的骨损耗的选择很少。因此，迫切需要 制定新的康复策略，以保存和/或恢复因脊髓损伤而失去的骨骼。这一点尤其正确 鉴于在神经肌肉康复方面正在取得重大进展(例如，利用运动神经元 功能恢复的可塑性和发芽/再生机制)；所有这些努力都岌岌可危 如果它们没有伴随着骨骼结构和强度的恢复，因为骨折可以使进展无效 在神经康复中制造的。尽管神经性骨丢失是一种不同于标准的疾病 绝经后骨质疏松症(PMO)或老年性骨质疏松症，目前还没有批准的治疗方法 针对脊髓损伤所致的骨丢失的后遗症。治疗脊髓损伤所致骨丢失的最接近的药物选择是 硬化素中和抗体Romosozumab(“Romo”)，由于其强大的合成代谢作用和在 脊髓损伤的小鼠模型。然而，Romo收到了FDA的黑匣子警告，警告其在 心血管疾病和中风风险较高的患者，这两个风险因素在 脊髓损伤患者。因此，尽管ROMO的建骨作用在脊髓损伤中是有益的，但它的充分利用是 不适合脊髓损伤患者。我们发现了一种联合疗法(硬化素和Dkk1中和疗法)， 减少83%的硬化素抗体剂量(和75%的总药物剂量)，但仍然保持所有 全强度硬化素抗体的骨代谢作用。我们的总体目标是利用互动 在一种非常特殊和新颖的骨合成代谢疗法(在我们的实验室中确认)和强大、持久的效果之间 机械刺激(运动)，以定义神经源性骨丢失的康复策略，将有 在大多数药物选择的短暂窗口之外的持久影响。我们的方法考虑到 考虑与脊髓损伤相关的危险因素(例如，心血管并发症增加和中风)和 运动对骨骼的有益作用和对运动功能的影响，设计出更具针对性和针对性的 脊髓损伤后骨骼康复的重点方法。在第一个目标中，我们将确定优化的 硬化素/Dkk1抗体治疗可恢复神经源性骨折后的骨密度、大小和强度 脊髓损伤导致的骨丢失。在第二个目标中，我们将确定优化的硬化素/Dkk1抗体 治疗可以使骨骼对脊髓损伤后的机械锻炼的效果敏感，产生更健壮和 耐折断的骨架。在第三个目标中，我们将确定持续的机械刺激是否可以 维持停用硬化素/Dkk1抗体治疗的有益骨骼效应，最终提供 脊髓损伤后骨骼维持的长期非药物解决方案。我们将同时评估 运动神经元和骨骼肌恢复，以及功能/行为结果，以评估 神经和肌肉恢复的治疗。AS(1)激活Wnt信号和(2)运动 对于轴突再生、肌肉生成和骨骼健康的治疗，我们提出的方法可能 对脊髓损伤患者有多系统的益处。