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; 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个膝盖骨关节炎（OA）是全球残疾的主要原因。疾病发展 2名退伍军人出现在年龄较小，人数高于人口 3一般。目前没有疾病改变抗骨关节炎药物（DMOAD） 4侧重于识别和跟踪射线照相OA结果而不是 5细胞前OA中的细胞和分子疾病途径。 TOPP协作功绩 6审查将检验中心假设，即OA疼痛和结构进展的异质性 7与OA的“免疫致病型”有关，这是由细胞中的变异性产生的 8骨，软骨和滑膜对炎症和关节机械的分子反应 9环境。总体具体目的是：目标1：提高对 10骨关节炎（OA）发病机理，以实现靶向早期治疗 11种方法；和目标2：为新的治疗靶标建立临床前和临床数据 12减轻疼痛并防止OA进展。实现这些目标需要完成 13和我们为员工提早和晚期OA临床人群的协作功绩的协同专业知识 14在VAHC和关节损伤动物模型中盛行，以定义OA的免疫病原体 15并测试新的治疗方法。这个特定的项目将建立一个队列 16例患有症状退化性射线照相OA的明显迹象的患者 17个半月板眼泪（DMT），以识别关节镜下部分疼痛和进展的预测指标 18拟切除术（APM）。退化弯月面撕裂（DMT）从中年开始普遍存在 19，可以在没有明显的射线照相膝骨OA的情况下发生。证据也越来越多 20表明，DMT可能会向膝盖向OA表型转变。类似于OA 21治疗，据报道，DMT患者的临床结局是高度可变的 22无论治疗是物理疗法，APM还是假手术。我们 23假设DMT治疗后的变量结果与是否与是否有关 24联合生物学已改用OA表型。该项目旨在通过 25确定2年后退伍军人膝盖疼痛和结构进展的生物学预测因子 26用APM治疗有症状的DMT。这项研究的目标1将测试术前滑膜 27由我们的初步数据和先前工作支持的OA生物标志物的流体水平（C2C，C1,2C， 28 COMP和CS846）预测DMT患者的膝盖疼痛和结构进展2年 APM之后29。 AIM 2将测试术前血清生物学标志物是否通过 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。 AIM 3将测试术前尿液UCTXII和UCTXIIA的水平是否预测膝盖 32 APM后2年，我们的DMT队列中的疼痛和结构进展。实现这一目标 33提案将为定义免疫病原体和 34人类OA的生物标志物。完成该项目还将有助于确定DMT是否 35例OA生物学特征的患者包括一个新型的早期OA队列。 36 VAHCS适用于评估新治疗策略的临床试验，以防止或延迟 37禁用OA的发作。这些结果支持总体假设和目标 38 TOPP协作功绩审查，并具有改善大型护理的高潜力 39名遭受膝盖OA的退伍军人和公众人数。