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

本申请的目的是确定一个长期的康复解决方案，以骨骼脆弱性相关的 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 人口神经源性骨质减少是SCI康复工作的主要并发症因素， 目前治疗脊髓损伤相关骨萎缩的选择很少。因此，迫切需要 开发新的康复策略，以保留和/或恢复因SCI而丢失的骨。尤其如此 考虑到在神经肌肉康复方面正在取得显著进展（例如，利用运动神经元 可塑性和发芽/再生机制）的功能恢复;所有这些努力都处于危险之中 如果它们不伴随着骨结构和强度的恢复，因为骨折可以使进展无效 神经康复治疗虽然神经性骨质流失是一种不同的疾病比标准 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SCI引起的骨丢失的后遗症。最接近SCI引起的骨丢失的药物选择是 硬化蛋白中和抗体Romosozumab（“Romo”），由于其有效的合成代谢作用和在抗硬化蛋白中的功效， SCI小鼠模型。然而，Romo收到了FDA的黑盒警告，警告其在 心血管疾病和中风风险较高的患者，这两种风险因素在 SCI患者因此，虽然Romo的骨生成作用对SCI有益，但其在全强度下的使用对SCI患者是不利的。 不适合SCI患者。我们已经发现了一种联合疗法（硬化素和Dkk 1中和）， 将硬化蛋白抗体剂量减少83%（和总药物剂量减少75%），但仍然保持所有的 全强度sclerostin抗体的骨合成代谢作用。我们的总体目标是利用 一个非常具体和新颖的骨合成代谢疗法（在我们的实验室确定），和强大的，持久的影响之间的关系， 机械刺激（运动），以确定神经性骨丢失的康复策略， 持久的影响超出了大多数药物选择的短暂窗口。我们的方法考虑到 考虑与SCI相关的风险因素（例如，心血管并发症和中风）， 锻炼对骨骼和运动功能的有益影响，以设计更有针对性的 专注于SCI后骨骼康复的方法。在第一个目标中，我们将确定优化的 硬化蛋白/Dkk 1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。 SCI导致的骨质流失。在第二个目标中，我们将确定优化的sclerostin/Dkk 1抗体是否 治疗可以使骨对SCI后机械运动的影响敏感，产生更强健， 耐腐蚀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 维持停止sclerostin/Dkk 1抗体治疗的有益骨骼作用， 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 神经和肌肉恢复的治疗。由于（1）Wnt信号的激活和（2）运动都是 治疗轴突再生，肌生成和骨骼健康，我们提出的方法很可能是 对SCI患者有多系统益处。

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.