CaMKK2 Signaling in Osteoarthritis

骨关节炎中的 CaMKK2 信号传导

• 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
• 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

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/文摘