CaMKK2 Signaling in Osteoarthritis

骨关节炎中的 CaMKK2 信号传导

• 批准号: 10577743
• 负责人: Uma Sankar
• 金额: $ 53.06万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577743
• 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; Cre lox recombination system; 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; Ligaments; Link; Macrophage; Medial meniscus structure; Mediating; Meniscus structure of joint; Mitogen-Activated Protein Kinases; Molecular; Morphology; Muramidase; Mus; Obesity; Operative Surgical Procedures; Osteitis; Osteoblasts; Osteoclasts; Outcome; Oxidative Stress; Pain; Pain management; Pathogenesis; Pathology; Pathway interactions; Persons; Phosphotransferases; Play; Process; Proliferating; Protein Kinase; Protein-Serine-Threonine Kinases; Regulation; Replacement Arthroplasty; Role; Signal Pathway; Signal Transduction; Sports; Surgical Models; Synovial Membrane; Synovitis; T-Lymphocyte; Tamoxifen; Testing; Tetracyclines; Therapeutic; Tissues; Trauma; Traumatic Arthropathy; aggrecan; articular cartilage; bone cell; cartilage degradation; cell type; curative treatments; cytokine; debilitating pain; functional disability; gain of function; healing; innovation; insight; joint injury; loss of function; mitochondrial dysfunction; mouse model; novel therapeutic intervention; overexpression; p38 Mitogen Activated Protein Kinase; pharmacologic; 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.

项目总结/摘要 骨关节炎是一种高度衰弱的疾病，影响全世界超过25万人。其 病因是多因素的，其中包括年龄、性别、肥胖、关节损伤和遗传。 关节软骨本质上是无法愈合自己。任何损伤都会导致其逐渐丧失，炎症 和痛苦. OA是整个关节的疾病，其病理包括软骨的进行性损失， 软骨下骨增厚、骨赘形成、滑膜炎症、韧带变性和 膝关节炎和关节囊肥大。调节OA的分子机制很差 明白目前没有有效的疾病修饰治疗可用于OA， 管理或手术关节置换术作为唯一的治疗选择。我们的初步研究发现 Ca2 +/CaM依赖性激酶激酶2（CaMKK2）是OA的潜在治疗靶点。关节 软骨细胞表达CaMKK2，其水平在OA中更高。基因消融或药物抑制 CaMKK2的表达可以防止软骨降解、滑膜炎症和软骨下骨改变， 手术诱导的OA小鼠模型。当用白细胞介素-1 β攻击时， Camkk2-/-小鼠表现出减弱的分解代谢和炎症反应，部分是通过下调 腺苷一磷酸依赖性蛋白激酶和p38丝裂原活化蛋白激酶信号传导 途径。基于这些数据，我们假设CaMKK 2协调软骨细胞对损伤的反应， 和炎性细胞因子，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。 目的1将研究在全基因敲除小鼠中观察到的对OA的保护是否来自于 CaMKK 2在软骨细胞中的细胞内在作用。目的2将阐明CaMKK 2 调节软骨细胞中的分解代谢和炎症反应。此外，CaMKK 2的缺乏或抑制 抑制巨噬细胞和破骨细胞。从这些细胞中有条件地缺失CaMKK2，如 目的3，将提供关于CaMKK 2如何在滑膜巨噬细胞和软骨下骨中发挥作用的见解 导致OA和/或影响软骨细胞对炎性细胞因子的反应。生成的信息 拟议研究将为开发CaMKK 2抑制剂作为一种新型治疗方法提供基础 治疗OA的方法。