BCCMA: Targeting Osteoarthritis Pain and Progression: Defining biologic and inflammatory markers associated with rapid progression

BCCMA：针对骨关节炎疼痛和进展：定义与快速进展相关的生物和炎症标志物

• 批准号: 10486497
• 负责人: CONSTANCE R CHU
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10486497
• 关键词: Age; Animal Model; Award; Biological; Biological Markers; Biology; Blood; Caring; Cartilage; Clinical; Clinical Data; Clinical Trials; Cluster Analysis; Collaborations; Data; Degenerative polyarthritis; Development; Disease; Disease Pathway; Early treatment; Environment; Funding; General Population; Goals; Healthcare Systems; Heterogeneity; Human; Image; Immune; Inflammation; Interleukin-13; Interleukin-4; Joints; Knee; Knee Osteoarthritis; Knowledge; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Mechanics; Modification; Molecular; Molecular Disease; Nerve; Nerve Growth Factors; Orthopedics; Outcome; Pain; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phenotype; Physical therapy; Plasma; Population; Precision therapeutics; Principal Component Analysis; Procedures; Proprotein Convertase 1; Proprotein Convertase 2; Proteins; Protocols documentation; Public Health; Relaxation; Reporting; Research Project Grants; Response to stimulus physiology; Roentgen Rays; Sampling; Scientist; Serum; Signal Transduction; Specimen; Stem Cell Factor; Stratification; Surgeon; Synovial Fluid; Synovial Membrane; Testing; Thick; Tissue Sample; United States National Institutes of Health; Urine; Veterans; Work; biomarker selection; bone; burden of illness; chronic pain; clinically relevant; cohort; cytokine; disability; early detection biomarkers; experience; follow-up; improved; inflammatory marker; interleukin-17E; joint injury; knee pain; mechanical stimulus; member; meniscal tear; middle age; multidisciplinary; new therapeutic target; novel; novel therapeutic intervention; osteoarthritis pain; pain reduction; pre-clinical; premature; prevent; prospective; radiological imaging; response; sham surgery; symptom treatment

1 Knee osteoarthritis (OA) is a leading cause of disability worldwide. Disease development in 2 Veterans occurs at significantly younger ages and at higher numbers than the population in 3 general. Currently there are no disease modifying anti-osteoarthritis drugs (DMOAD) due in part 4 to a historical focus on identification and tracking of radiographic OA outcomes rather than 5 cellular and molecular disease pathways in pre-radiographic OA. The TOPP Collaborative Merit 6 Review will test the central hypothesis that heterogeneity in OA pain and structural progression 7 is related to the “immune pathotype” of OA, which arises from the variability in the cellular and 8 molecular responses of bone, cartilage, and synovium to inflammation and joint mechanical 9 environment. The overarching Specific Aims are: Aim 1: To improve understanding of 10 osteoarthritis (OA) pathogenesis to enable development of targeted early treatment 11 approaches; and Aim 2: To establish preclinical and clinical data for new therapeutic targets to 12 reduce pain and prevent OA progression. Achieving these Aims requires the complementary 13 and synergistic expertise of our Collaborative Merit to employ early and late OA clinical cohorts 14 prevalent in the VAHCS and joint injury animal models to define the immune pathotypes of OA 15 and to test novel therapeutic approaches. This particular project will establish a cohort of 16 patients without significant signs of radiographic OA who suffer from symptomatic degenerative 17 meniscus tears (DMT) to identify predictors of pain and progression after arthroscopic partial 18 meniscectomy (APM). Degenerative meniscus tears (DMT) are prevalent starting in middle age 19 and can occur in the absence of significant radiographic knee OA. Growing evidence also 20 suggests that the DMT may signal transition of the knee to an OA phenotype. Similar to OA 21 treatment, clinical outcomes for DMT patients have been reported to be highly variable 22 irrespective of whether treatment is with physical therapy, APM, or sham surgery. We 23 hypothesize that the variable results following APM treatment of DMT are related to whether 24 joint biology has switched to an OA phenotype. This project aims to test this hypothesis by 25 identifying biological predictors of knee pain and structural progression in Veterans 2 years after 26 treatment of symptomatic DMT with APM. Aim 1 of this study will test if preoperative synovial 27 fluid levels of OA biomarkers supported by our preliminary data and prior work (C2C, C1,2C, 28 COMP and CS846) predict knee pain and structural progression in DMT patients 2 years 29 following APM. Aim 2 will test if preoperative serum biological markers implicated in OA pain by 30 our preliminary data (IL-4, IL-13, and IL-17E) predict knee pain and structural progression 2 31 years after APM. Aim 3 will test if preoperative levels of urine uCTXII and uCTXIIa predict knee 32 pain and structural progression in our DMT cohort 2 years after APM. Achieving the Aims of this 33 proposal will contribute new information important to defining immune pathotypes and 34 biomarkers of early human OA. Completing this project will also help determine whether DMT 35 patients with biological signatures of OA comprise a novel early OA cohort prevalent within the 36 VAHCS suitable for clinical trials evaluating new treatment strategies to prevent or delay the 37 onset of disabling OA. These outcomes support the overarching hypothesis and Aims of the 38 TOPP Collaborative Merit Review and have high potential to improve the care of the large 39 number of Veterans and members of the general public who suffer from knee OA.

1 膝骨关节炎 (OA) 是全世界残疾的主要原因。疾病发展于 2 退伍军人的年龄明显低于美国人口，而且数量也较多 3 一般。目前尚无缓解疾病的抗骨关节炎药物 (DMOAD)，部分原因是 4 历史上重点关注放射学 OA 结果的识别和跟踪，而不是 放射照相前 OA 中的 5 种细胞和分子疾病途径。 TOPP 协作优点 6 审查将检验骨关节炎疼痛和结构进展的异质性这一中心假设 7 与 OA 的“免疫病理型”有关，这是由细胞和细胞的变异性引起的。 骨、软骨和滑膜对炎症和关节机械的 8 种分子反应 9 环境。总体具体目标是： 目标 1：增进对 10 骨关节炎 (OA) 发病机制有助于开发有针对性的早期治疗 11 种方法；目标 2：为新的治疗靶点建立临床前和临床数据 12 减轻疼痛并预防骨关节炎进展。实现这些目标需要互补 13 我们的协作优势的协同专业知识可利用早期和晚期 OA 临床队列 14 VAHCS 和关节损伤动物模型中普遍存在的 OA 免疫病理类型 15 并测试新的治疗方法。这个特殊项目将建立一批 16 名无明显放射学 OA 体征但患有症状性退行性病变的患者 17 半月板撕裂 (DMT) 用于确定关节镜部分术后疼痛和进展的预测因素 18 半月板切除术（APM）。退行性半月板撕裂 (DMT) 从中年开始普遍存在 19 并且可以在没有明显的放射学膝关节 OA 的情况下发生。越来越多的证据也 图20表明DMT可能发出膝盖向OA表型转变的信号。类似于办公自动化 据报道，21 种治疗方法，DMT 患者的临床结果差异很大 22 无论治疗是采用物理疗法、APM 还是假手术。我们 23 假设 APM 治疗 DMT 后的可变结果与是否 24 关节生物学已转变为 OA 表型。该项目旨在通过以下方式检验这一假设 2 年后确定退伍军人膝盖疼痛和结构进展的 25 个生物预测因子 26 用 APM 治疗有症状的 DMT。本研究的目标 1 将测试术前滑膜是否 我们的初步数据和之前的工作支持 27 种液体水平的 OA 生物标志物（C2C、C1、2C、 28 COMP 和 CS846) 预测 DMT 患者 2 年膝关节疼痛和结构进展 29 以下 APM。目标 2 将测试术前血清生物标志物是否与 OA 疼痛有关 30 我们的初步数据（IL-4、IL-13 和 IL-17E）预测膝盖疼痛和结构进展2 APM 31 年后。目标 3 将测试术前尿液 uCTXII 和 uCTXIIa 水平是否可以预测膝关节 32 APM 后 2 年，我们的 DMT 队列中出现疼痛和结构进展。实现本次活动的目标 33 提案将为定义免疫病理型提供重要的新信息 早期人类 OA 的 34 种生物标志物。完成该项目还将有助于确定 DMT 是否 35 名具有 OA 生物学特征的患者构成了一个新的早期 OA 队列，该队列在 36 VAHCS 适合临床试验，评估新的治疗策略，以预防或延迟 37 开始出现禁用性 OA。这些结果支持总体假设和目标 38 TOPP 协作优点评审，具有改善大型患者护理的巨大潜力 39 名退伍军人和普通公众患有膝骨关节炎。