CaMKK2 Signaling in Osteoarthritis

骨关节炎中的 CaMKK2 信号传导

基本信息

批准号：
10348741
负责人：
Uma Sankar
金额：
$ 52.53万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/10348741
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 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 Persons Pharmacology Phosphotransferases Play Process 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 aggrecan articular cartilage base bone cell cartilage degradation cell type curative treatments cytokine debilitating pain 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

项目摘要

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.

项目概要/摘要骨关节炎是一种使人严重衰弱的疾病，影响着全世界超过 25 万人。病因是多因素的，其中包括年龄、性别、肥胖、关节损伤和遗传等因素。关节软骨本质上无法自行愈合，任何损伤都会导致其逐渐丧失、炎症。 OA 是一种整个关节的疾病，其病理包括软骨的进行性丧失，软骨下骨增厚、骨赘形成、滑膜炎症、韧带变性膝关节半月板和关节囊肥大调节 OA 的分子机制较差。据了解，目前尚无有效的缓解 OA 疾病的治疗方法，从而导致疼痛。我们的初步研究表明，治疗或手术关节置换是唯一的治疗选择。 Ca2+/CaM 依赖性激酶激酶 2 (CaMKK2) 作为 OA 的潜在治疗靶点。软骨细胞表达 CaMKK2，其水平在 OA 中较高。 CaMKK2 可以防止软骨退化、滑膜炎症和软骨下骨改变手术诱导的 OA 小鼠模型，当受到白细胞介素 1β 攻击时，关节软骨细胞 Camkk2-/- 小鼠表现出减弱的分解代谢和炎症反应，部分是通过下调单磷酸腺苷依赖性蛋白激酶和 p38 丝裂原激活蛋白激酶信号传导基于这些数据，我们确信 CaMKK2 可以协调软骨细胞对损伤的反应。和炎症细胞因子，其在软骨细胞中的功能在 OA 的发生发展中起着至关重要的作用。目标 1 将研究在全局基因敲除小鼠中观察到的 OA 保护是否来自 CaMKK2 在软骨细胞中的细胞内在作用。目标 2 将阐明 CaMKK2 的机制。此外，CaMKK2 的缺失或抑制可调节软骨细胞的分解代谢和炎症反应。抑制巨噬细胞和破骨细胞，有条件地从这些细胞中删除 CaMKK2，如提出的。目标 3，将提供有关 CaMKK2 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症细胞因子的反应。拟议的研究将为开发 CaMKK2 抑制作为治疗新药奠定基础治疗 OA 的方法。