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.

本申请的目的是确定一种长期康复解决方案，以解决与骨骼脆弱相关的问题 脊髓损伤 (SCI) 是退伍军人中最令人衰弱的疾病之一。 神经源性骨质减少是 SCI 康复工作的一个主要复杂因素。 目前治疗 SCI 相关骨消耗的选择很少，因此迫切需要治疗。 制定新的康复策略来保存和/或恢复 SCI 造成的骨质流失尤其如此。 鉴于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 可塑性和发芽/再生机制）用于功能恢复；所有这些努力都处于危险之中； 如果没有伴随骨骼结构和强度的恢复，因为骨折会抵消进展 尽管神经源性骨质流失是一种与标准疾病不同的疾病。 绝经后骨质疏松症（PMO）或老年性骨质疏松症，目前尚无批准的治疗方法专门针对 针对 SCI 引起的骨质流失的后遗症，治疗 SCI 引起的骨质流失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功效 然而，Romo 收到了 FDA 的黑框警告，警告其在 SCI 小鼠模型中的使用。 心血管疾病和中风风险较高的患者，这两个危险因素在 因此，虽然 Romo 的骨质增强作用对 SCI 患者有益，但充分使用它是有风险的。 我们发现了一种联合疗法（硬化素和 Dkk1 中和），不适合 SCI 患者。 将硬化素抗体剂量减少 83%（总药物剂量减少 75%），但仍保持所有 全强度硬化素抗体的骨合成代谢作用我们的总体目标是利用相互作用。 非常具体和新颖的骨合成代谢疗法（在我们的实验室中确定）与强大、持久的效果之间的关系 机械刺激（运动），以确定神经源性骨质流失的康复策略 我们的方法考虑到了大多数药物选择的短暂窗口之外的持久效果。 考虑与 SCI 相关的危险因素（例如心血管并发症和中风升高）以及 锻炼对骨骼和运动功能的有益影响，以设计更量身定制的和 SCI 后骨骼康复的重点方法 第一个目标是确定是否优化。 硬化蛋白/Dkk1 抗体的比例治疗可以恢复神经源性后的骨骼密度、大小和强度 在第二个目标中，我们将确定是否优化了 sclerostin/Dkk1 抗体。 治疗可以使骨骼对 SCI 后机械运动的影响敏感，从而产生更坚固和更坚固的骨骼。 在第三个目标中，我们将确定持续的机械刺激是否可以。 维持已停止的硬化素/Dkk1 抗体治疗的有益骨骼效应，最终提供 SCI 后骨骼维护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/行为结果以评估效果 对于神经和肌肉恢复的治疗，如（1）Wnt 信号的激活和（2）运动都是如此。 对于轴突再生、肌生成和骨骼健康的治疗，我们提出的方法可能 对 SCI 患者具有多系统益处。