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膝关节骨关节炎（OA）是全球残疾的主要原因。疾病发展 2.退伍军人的年龄明显比美国人口年轻，人数也比美国人口多。 3一般。目前还没有部分原因是疾病修饰抗骨关节炎药物（DMOAD） 4到历史上侧重于识别和跟踪放射学OA结局，而不是 影像学检查前OA的5种细胞和分子疾病途径。TOPP协作优势 6综述将检验中心假设，即OA疼痛和结构进展的异质性 7与OA的“免疫病理型”有关，其产生于细胞和免疫系统的变异性。 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：提高对 10骨关节炎（OA）发病机制，使有针对性的早期治疗的发展 目标2：建立新的治疗靶点的临床前和临床数据， 12减轻疼痛，防止OA进展。要实现这些目标，就需要 13和我们的协作优势的协同专业知识，采用早期和晚期OA临床队列 14种在VAHCS和关节损伤动物模型中普遍存在，以定义OA的免疫病理类型 15和测试新的治疗方法。这个特别的项目将建立一个队列， 16例无显著影像学OA体征的患者，患有症状性退行性关节炎 17例半月板撕裂（DMT），以确定关节镜部分切除术后疼痛和进展的预测因素 18例阑尾切除术（APM）。退行性半月板撕裂（DMT）在中年开始流行 19并且可能发生在没有明显放射学膝关节OA的情况下。越来越多的证据表明， 20表明DMT可能是膝关节向OA表型转变的信号。类似于OA 21治疗，DMT患者的临床结局据报道是高度可变的 22无论治疗是物理治疗，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个关节生物学已转换为OA表型。该项目旨在通过以下方式验证这一假设： 25确定退伍军人2年后膝盖疼痛和结构性进展的生物学预测因素 26例用APM治疗症状性DMT。本研究的目的1将测试术前滑膜是否 我们的初步数据和先前工作支持的27种OA生物标志物的液体水平（C2C，C1，2C， 28 COMP和CS 846）预测DMT患者2年后的膝关节疼痛和结构进展 第29话APM目的2将通过以下方法测试术前血清生物学标记物是否与OA疼痛有关： 30我们的初步数据（IL-4、IL-13和IL-17 E）预测膝关节疼痛和结构进展2 APM之后的31年目标3将测试术前尿uCTXII和uCTXIIa水平是否可预测膝关节置换术 APM后2年，我们的DMT队列中有32例疼痛和结构进展。实现这一目标 33项提案将为定义免疫病理类型提供重要的新信息， 早期人类OA的34种生物标志物。完成这个项目也将有助于确定DMT是否 35例具有OA生物学特征的患者组成了一个新的早期OA队列， 36个VAHCS适用于临床试验，评估新的治疗策略，以预防或延迟 37例致残性OA发作。这些结果支持了总体假设和目标， 38 TOPP协作优点审查，并有很大的潜力，以改善护理的大 39名退伍军人和普通公众患有膝关节OA。