"Novel therapeutic approaches to improve fracture healing while reducing pain behavior"

骨折的退伍军人遭受损伤相关的疼痛以及手术后的疼痛。的 骨折的发生导致急性疼痛，并且主要表现为机械性、炎性和 神经病变成分。高能量下肢创伤的LEAP研究表明，急性疼痛， 严重创伤后的恢复期是5 - 10年长期慢性疼痛的最大预测因素 伤后治疗创伤引起的疼痛和手术后疼痛有两种主要策略：阿片类药物和 非甾体抗炎药（NSAID）。两种药物都不能完全缓解疼痛， 负面的副作用阿片类药物，除了引起认知障碍，通常与耐受性有关 和上瘾。NSAID通常在胸/腹部手术后与阿片类药物联合使用 但由于对骨骼健康的负面影响，在美国不鼓励使用这种药物治疗骨折疼痛 和愈合受伤的骨骼。目前还不清楚哪类药物对骨修复过程的破坏性较小 但在骨折治疗中，预防骨不连是最重要的，因为它给患者带来了额外的负担， 患者和医疗保健系统由于长期的疼痛和残疾。因此，确定治疗方法 其改善了骨愈合过程并减少了骨相关的疼痛。我们 最近的数据表明，Sirtuin-1（Sirt1，一种NAD + III类组蛋白脱乙酰酶）的mRNA水平是 在骨折愈合过程中明显升高。骨折愈合随着年龄、骨质流失、炎症和 神经退化重要的是，Sirt1改善了所有这些条件;然而，据我们所知， 除了我们的研究，没有人专门研究Sirt1对骨折修复的影响。这里我们 显示SRT 1720对Sirt1药理学激活允许改善骨折愈合，同时减少 疼痛行为基于这些观察，我们假设间充质细胞中Sirt1的激活 谱系细胞和相关的神经系统相互作用将增强骨愈合并减少疼痛， 小鼠通过调节炎症。拟议的工作将测试这一假设，并可能提供证据， Sirt1的药理学激活可以作为一种新的骨愈合剂和骨折后镇痛剂 剂在目标1中，我们将证明SRT 1720可以改善骨愈合并减少疼痛行为， 炎症，并确定哪些细胞需要SRT 1720激活Sirt1才能成功骨形成 愈合，减少疼痛行为和减少炎症。在目标2中，我们将确定SRT 1720 治疗、间充质谱系细胞和初级传入感觉神经元（PAN）调节炎症， 我们将研究间充质谱系细胞和PAN之间的串扰。成功完成 这些目的将证明使用Sirt1激活剂作为新的骨愈合和骨折后 镇痛剂后者，可以取代阿片类药物用于疼痛管理的必要性，作为一种治疗疼痛的方法。 这是对抗阿片类药物危机的重要一步，可以显着改善患者的预后。

Veterans with fractures suffer from injury-associated pain as well as post-operative surgical pain. The occurrence of a fracture contributes to acute pain and is largely manifested by mechanical, inflammatory, and neuropathic components. The LEAP study of high-energy lower extremity trauma showed that acute pain, in the recovery period after severe trauma, is the single largest predictor of long-term chronic pain 5-10 years after injury. There are 2 main strategies to treat trauma-induced and post-surgical pain: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Neither drug class completely alleviates pain, and both have negative side effects. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. NSAIDs are commonly used in combination with opioids following thoracic/abdominal surgery but use of this drug class for fracture pain is discouraged in the U.S. due to negative effects on skeletal health and healing of the injured skeleton. It is unclear which drug class is less destructive to the bone repair process but prevention of nonunion is paramount in the treatment of fractures as it places additional burden on the patient and the healthcare system due to prolonged pain and disability. Therefore, identification of therapies which improve both the bone healing process and diminish the fracture-associated pain is warranted. Our recent data demonstrate that mRNA levels of Sirtuin-1 (Sirt1, an NAD+ class III histone deacetylase) are robustly elevated during fracture healing. Fracture healing is impaired with age, bone loss, inflammation, and with neurodegeneration. Importantly, Sirt1 improves all of these conditions; however, to our knowledge, with the exception of our studies, nobody has specifically examined the effects of Sirt1 on fracture repair. Here we show that pharmacological activation of Sirt1 by SRT1720 allows for improved fracture healing while reducing pain behaviors. Based on these observations we hypothesize that activation of Sirt1 in mesenchymal lineage cells and associated nervous system interactions will enhance bone healing and reduce pain in mice by regulating inflammation. The proposed work will test this hypothesis, and may provide evidence that pharmacologic activation of Sirt1 could serve both as a novel bone healing agent and post-fracture analgesic agent. In Aim 1, we will demonstrate that SRT1720 can improve bone healing and reduce pain behaviors and inflammation in mice, and determine which cells require Sirt1 activation by SRT1720 for successful bone healing, reduced pain behaviors, and reduced inflammation. In Aim 2, we will determine how SRT1720 treatment, mesenchymal lineage cells, and primary afferent sensory neurons (PANs) regulate inflammation, and we will examine the crosstalk between mesenchymal lineage cells and PANs. Successful accomplishment of these Aims will demonstrate the utility of using Sirt1 activators as novel bone healing and post-fracture analgesic agents. The latter, could replace the necessity of opioids for pain management, serve as an important step in fighting the opioid crisis, and could significantly improve patient outcomes.