BCCMA: Targeting Osteoarthritis Pain and Progression: Preclinical OA models of vagal nerve stimulation to reduce pain and progression of OA

项目总结： 在退伍军人中，骨性关节炎是慢性疼痛和残疾的主要原因，他们在非常年轻的时候就发展成骨性关节炎 年龄和人数都高于非退伍军人。因此，骨性关节炎的疾病负担不成比例。 由退伍军人和退伍军人医疗系统(VAHCS)承担。目前还没有疾病修饰的抗 骨关节炎药物(DMOAD)的部分原因是历史上对放射性骨性关节炎的识别和跟踪的关注 结果，而不是疼痛和功能相关的疾病途径。我们在治疗中的综合研究计划 骨关节炎疼痛和进展(TOPP)协作优点计划将检验以下中心假设 骨性关节炎疼痛和结构进展的变异性与细胞和分子的异质性有关 骨、软骨和滑膜对炎症和关节负荷的反应。这一协作优势将 追求两个压倒一切的具体目标：目标1：提高对骨关节炎(OA)发病机制的了解 能够开发有针对性的治疗方法，目标2：建立新的临床前数据 治疗目标是减轻疼痛和防止骨性关节炎的进展。使用早期和晚期骨性关节炎临床队列 在VAHCS和关节损伤动物模型中流行以测试新的治疗方法将需要 协调多学科工作台到床边工作，这是任何一个项目都不能充分解决的。此外， 我们将结合针对神经生长因子的迷走神经刺激(VNS)的治疗效果的结果 (NGF)和以肥大细胞为靶点的临床前骨性关节炎动物模型中的人骨性关节炎表型和分层 将允许快速过渡到骨性关节炎和关节损伤的临床试验。项目4的目标是确定 经皮迷走神经刺激(TVNS)减轻疼痛并防止结构进展 急、慢性临床前骨性关节炎模型。VNS，目前FDA批准用于癫痫和抑郁症， 激活胆碱素抗炎途径，推动神经和非神经细胞产生乙酰胆碱(Ach) 神经细胞，并提供强大的全身性抗炎作用，减少滑膜炎症和 类风湿性关节炎小鼠模型的关节疼痛。在关节内，胆碱能纤维支配滑膜， 骨小梁和骨膜，研究表明副交感神经系统调节 伤害性疼痛和可能的骨性关节炎发病机制。巨噬细胞烟碱型乙酰胆碱受体α7(α7NAChR)的表达 T细胞和软骨细胞可能参与了VNS效应。基于这些和我们令人兴奋的初步数据显示 在失稳的内侧半月板损伤模型中，VNS治疗4周后疼痛改善，我们的假设是tVNS 减少疼痛，防止骨性关节炎的结构进展。我们将从三个方面检验这一假设：(1)检验是否 TVNS减轻急性和慢性骨性关节炎小鼠模型的疼痛，(2)测试tVNS是否减缓骨关节炎的结构进展 急性和慢性骨性关节炎小鼠模型，以及(3)TVNS在骨性关节炎动物模型和人类中的综合结果 OA表型分型以确定预测VNS反应或OA进展的生物标志物。结果将有一个 通过提供关键的临床前证据证明VNS可以改善疼痛和 防止骨性关节炎的进展，并将提供重要的人类生物标志物来改善对患有骨性关节炎患者的选择 用于VNS和其他新兴治疗的临床试验的早期或晚期OA。

Project Summary: OA is a leading cause of chronic pain and disability in our Veterans who develop OA at significantly younger ages and in higher numbers than non-Veterans. Consequently, the disease burden of OA is disproportionately borne by Veterans and the VA Healthcare system (VAHCS). Currently there are no disease modifying anti- osteoarthritis drugs (DMOAD) due in part to a historical focus on identification and tracking of radiographic OA outcomes rather than pain and function-related disease pathways. Our integrated research program in the Treat Osteoarthritis Pain and Progression (TOPP) Collaborative Merit program will test the central hypothesis that variability in OA pain and structural progression is related to heterogeneity in the cellular and molecular responses of bone, cartilage, and synovium to inflammation and joint loading. This Collaborative Merit will pursue two overarching Specific Aims: Aim 1: To improve understanding of osteoarthritis (OA) pathogeneses to enable development of targeted therapeutic approaches, and Aim 2: To establish preclinical data for new therapeutic targets to reduce pain and prevent OA progression. Using early and late OA clinical cohorts prevalent in the VAHCS and joint injury animal models to test novel therapeutic approaches will require coordinated multidisciplinary bench to bedside work for that no single project can adequately address. Further, we will couple results from treatment efficacy of vagal nerve stimulation (VNS), targeting nerve growth factor (NGF), and targeting mast cells in preclinical OA animal models with human OA phenotyping and stratification will allow for rapid transition to clinical trials in OA and joint injury. The goal of Project 4 is to determine if transcutaneous vagal nerve stimulations (tVNS) reduces pain and prevents structural progression in acute and chronic preclinical OA models. VNS, currently FDA approved for epilepsy and depression, activates a cholingeric anti-inflammatory pathway, driving production of acetylcholine (Ach) in nerves and non- neuronal cells, and provides a strong systemic anti-inflammatory effect that reduces synovial inflammation and joint pain in mouse models of rheumatoid arthritis. Within the joint, cholinergic fibers innervate the synovium, trabecular bone, and periosteum and studies suggest that the parasympathetic nervous system modulates nociceptive pain and possibly OA pathogenesis. Nicotinic acetylcholine receptor α7 (α7NAChR) in macrophages, T cells, and chondrocytes may mediate VNS effects. Based on these and our exciting preliminary data showing improved pain after 4 weeks of VNS in the destabilized medial meniscal injury model, our hypothesis is that tVNS reduces pain and prevents structural progression in OA. We will test this hypothesis in three aims: (1) Test if tVNS reduces pain in acute and chronic mouse models of OA, (2) test if tVNS slows structural progression of acute and chronic mouse models of OA, and (3) Integrate outcomes of tVNS in OA animal models with human OA phenotyping to identify biomarkers predictive of VNS response or OA progression. Results will have a substantial impact on Veteran Health by providing critical preclinical evidence that VNS improves pain and prevents progression of OA and will provide important human biomarkers to improve selection of patients with early or late-stage OA for clinical trials of VNS and other emerging treatments.