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AMPK as an Interventional Target to Suppress the Development of Osteoarthritis

AMPK 作为抑制骨关节炎发展的干预靶点

基本信息

批准号：
8727797
负责人：
RU BRYAN
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-10-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727797
关键词：
5&apos -AMP-activated protein kinase Affect Age Aging Anabolism Apoptosis Arthritis Attenuated Berberine Biogenesis Biomechanics C57BL/6 Mouse Cartilage Cartilage Matrix Catabolism Catalytic Domain Cells Cessation of life Characteristics Chondrocytes Degenerative polyarthritis Development Disease Energy Metabolism Environment Equilibrium Exercise Exhibits Failure Foundations Functional disorder Healthcare Homeostasis Human Hypoxia In Vitro Inflammation Inflammatory Injury Joints Knee Knee Osteoarthritis Knockout Mice Link Medial meniscus structure Mediating Medical Metabolism Mitochondria Modeling Molecular Mus Nutrient Operative Surgical Procedures Oxidative Stress Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Plant alkaloid Plants Process Protein Isoforms Public Health Research Design Risk Risk Factors Role Services Site Testing Therapeutic Therapeutic Intervention Threonine Tissues Traditional Medicine Translations Veterans Wild Type Mouse age group arthropathies articular cartilage cartilage degradation cell type cytokine deprivation design dietary supplements disability high risk improved in vivo insight joint injury mitochondrial dysfunction mouse development normal aging novel novel strategies novel therapeutic intervention overexpression prevent public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common joint disorder and a leading cause of disability. Age and joint injury are among the primary risk factors for OA development. Since many Veterans are older and/or had traumatic joint injury when in service, they are at high risk to develop OA. However, there are yet no effective medical therapies to delay and/or limit OA development and progression, and this is an urgent medical need. Progressive degeneration of articular cartilage is a major characteristic of the disease. Chondrocyte, the only cell type residing in the cartilage matrix, regulate the homeostatic balance between matrix synthesis and degradation, which fails in OA. Thus, one approach to rationally designed new OA therapies is to improve chondrocyte function by targeting pathogenesis of the disease. AMP-activated protein kinase (AMPK) is a "super-regulator" of energy homeostasis and cellular metabolism. We recently discovered that AMPK activity is constitutively present in normal articular chondrocytes, but is decreased in OA chondrocytes, correlated with increased catabolic responses. In addition, loss of AMPK activity in chondrocytes is associated with inflammation, biomechanical injury and aging. Moreover, pharmacologic activation of AMPK not only attenuates pro-catabolic responses to inflammatory cytokines and biomechanical injury, but also promotes mitochondrial biogenesis and protects chondrocytes from oxidative stress. Furthermore, in our preliminary in vivo studies, we observed that berberine, a natural plant product used as traditional medicine and dietary supplement, and known to active AMPK, significantly limits mice from development of knee OA induced by surgical destabilization of medial meniscus (DMM). Building on these findings, we propose to test our central hypotheses that sustained AMPK activity is critical to articular cartilage homeostasis and that AMPK is a potential interventional target to delay and/or limit the onset and progression of OA. We specifically aim to: (1) Define how AMPK activation is chondroprotective in vitro at the molecular level. (2) Determine if reduced AMPK activity in human knee articular cartilage, particularly in the superficial zone where cartilage degeneration appears to be initiated in OA, is a fundamental change in normal aging, providing a platform for OA development and progression. (3) Test the hypothesis that molecularly selective loss of AMPK activity promotes OA development and progression in mice in vivo (4) Test the translational hypothesis that therapeutic induction of AMPK activity by the highly selective AMPK activator A-769662 delays and/or limits the development and progression of spontaneous OA in vivo using the STR/ort mice (an established model for spontaneous OA that resembles human OA). Completion of these studies will provide new insights into how changes in chondrocyte bio-energetics affects cartilage homeostasis, and aid to develop a new therapeutic approach by targeting at AMPK to suppress the development and progression of OA.

描述（由申请人提供）：