CaMKK2 Signaling in Osteoarthritis

骨关节炎中的 CaMKK2 信号传导

• 批准号: 10376643
• 负责人: Uma Sankar
• 金额: $ 31.39万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-13 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376643
• 关键词: Ablation; Adenosine Monophosphate; Affect; Age; Apoptosis; Attenuated; Bone Spur; Bone remodeling; Ca(2+)-Calmodulin Dependent Protein Kinase; Cartilage; Cells; Cellular Metabolic Process; Chondrocytes; Complex; Data; Deformity; Degenerative polyarthritis; Development; Disease; Disease Progression; Down-Regulation; Elderly; Etiology; Family member; Gender; Generations; Genetic; Goals; Heredity; Hypertrophy; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Investigation; Joint Capsule; Joints; Knee; Knockout Mice; Lead; Ligaments; Link; Longitudinal Studies; MAP Kinase Gene; Medial meniscus structure; Mediating; Meniscus structure of joint; Molecular; Morphology; Muramidase; Mus; Obesity; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Outcome; Oxidative Stress; Pain; Pain management; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phosphotransferases; Play; Process; Protein Kinase; Protein-Serine-Threonine Kinases; Regulation; Replacement Arthroplasty; Role; Signal Pathway; Signal Transduction; Sports; Surgical Models; Synovial Membrane; Synovitis; System; T-Lymphocyte; Tamoxifen; Testing; Tetracyclines; Therapeutic; Tissues; Trauma; aggrecan; articular cartilage; base; bone cell; cartilage degradation; cell type; curative treatments; cytokine; functional disability; gain of function; healing; innovation; insight; joint injury; macrophage; mitochondrial dysfunction; mouse model; novel therapeutic intervention; overexpression; p38 MAPK Signaling Pathway; p38 Mitogen Activated Protein Kinase; prevent; response; response to injury; subchondral bone; therapeutic target

PROJECT SUMMARY/ABSTRACT Osteoarthritis is a highly debilitating disease affecting more than a quarter million people worldwide. Its etiology is multifactorial, with age, gender, obesity, joint injury and heredity among the contributing factors. Articular cartilage is intrinsically unable to heal itself. Any damage results in its progressive loss, inflammation and pain. OA is a disease of the entire joint, and its pathology includes the progressive loss of cartilage, subchondral bone thickening, osteophyte formation, synovial inflammation, degeneration of ligaments and knee menisci, and hypertrophy of the joint capsule. Molecular mechanisms regulating OA are poorly understood. No effective disease-modifying treatments are currently available for OA, leaving pain management or surgical joint replacement as the only therapeutic options. Our preliminary studies identify Ca2+/CaM-dependent kinase kinase 2 (CaMKK2) as a potential therapeutic target against OA. Articular chondrocytes express CaMKK2 and its levels are higher in OA. Genetic ablation or pharmacological inhibition of CaMKK2 protects against cartilage degradation, synovial inflammation, and subchondral bone alterations in a murine model of surgically induced OA. When challenged with interleukin-1β, articular chondrocytes from Camkk2-/- mice display attenuated catabolic and inflammatory responses, in part through downregulation of the adenosine mono-phosphate dependent protein kinase and p38 mitogen activated protein kinase signaling pathways. Based on these data, we hypothesize that CaMKK2 coordinates chondrocyte-responses to injury and inflammatory cytokines, and its function in chondrocytes plays a crucial role in the development of OA. Aim 1 will investigate whether the protection from OA as observed in the global knockout mice comes from the cell-intrinsic role of CaMKK2 in chondrocytes. Aim 2 will elucidate the mechanisms by which CaMKK2 regulates catabolic and inflammatory responses in chondrocytes. Further, absence or inhibition of CaMKK2 suppresses macrophages and osteoclasts. Conditional deletion of CaMKK2 from these cells, as proposed in Aim 3, will provide insights on how CaMKK2 function in synovial macrophages and subchondral bone contribute to OA, and/or influence chondrocyte responses to inflammatory cytokines. Information generated from the proposed studies will provide a basis for developing CaMKK2 inhibition as a novel therapeutic approach to treat OA.

项目摘要/摘要 骨关节炎是一种高度令人衰弱的疾病，影响了全球超过25万人。它是 病因是多因素，与促成因素之间的年龄，性别，肥胖，关节损伤和遗产。 关节软骨本质上是无法修复的。任何损害导致其逐渐损失，炎症 和痛苦。 OA是整个关节的一种疾病，其病理包括软骨的进行性丧失， 软骨下骨增厚，骨质植物的形成，滑膜感染，韧带变性和 膝盖弯曲和关节囊的肥大。调节OA的分子机制很差 理解齿。目前没有有效的疾病改良治疗可用于OA，留下疼痛 管理或手术关节替代是唯一的治疗选择。我们的初步研究确定 Ca2+/CAM依赖性激酶激酶2（CAMKK2）是针对OA的潜在治疗靶标。艺术 软骨细胞表达CAMKK2及其水平在OA中较高。遗传消融或药理抑制 CAMKK2防止软骨降解，滑膜注射和软骨下骨改变 手术诱导的OA的鼠模型。当通过白介素1β挑战时，关节软骨细胞来自 CAMKK2 - / - 小鼠显示出减弱的分解代谢和炎症反应，部分通过下调 腺苷单磷酸依赖性蛋白激酶和p38有丝分裂激活的蛋白激酶信号传导 途径。基于这些数据，我们假设CAMKK2坐在软骨细胞反应中损伤 炎性细胞因子及其在软骨细胞中的功能在OA的发展中起着至关重要的作用。 AIM 1将调查全球敲除小鼠中观察到的OA的保护是否来自 CAMKK2在软骨细胞中的细胞中性作用。 AIM 2将阐明CAMKK2的机制 调节软骨细胞中的分解代谢和炎症反应。此外，CAMKK2的缺失或抑制 抑制巨噬细胞和破骨细胞。如在这些细胞中的有条件删除CAMKK2，如 AIM 3将提供有关CAMKK2在滑膜巨噬细胞和软骨下骨中如何发挥作用的见解 有助于OA和/或影响软骨细胞对炎症细胞因子的反应。生成的信息 根据拟议的研究，将为开发CAMKK2抑制作用作为一种新的疗法提供基础 治疗OA的方法。