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

• 批准号: 9232963
• 负责人: RU BRYAN
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 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/9232963
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; Aging; Anabolism; Apoptosis; Arthritis; Attenuated; Berberine; Bioenergetics; 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; Intervention; Joints; Knee; Knee Osteoarthritis; Knockout Mice; Link; Medial meniscus structure; Mediating; Medical; Metabolism; Mitochondria; Modeling; Molecular; Mus; Nutritional; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Plant alkaloid; Plants; Process; Protein Isoforms; Protein Kinase; Public Health; Risk; Risk Factors; Role; SIRT1 gene; Services; Site; Testing; Therapeutic; Therapeutic Intervention; Threonine; Tissues; Traditional Medicine; Translations; Treatment Efficacy; Veterans; Wild Type Mouse; age group; arthropathies; articular cartilage; cartilage degradation; cell type; cytokine; design; dietary supplements; disability; high risk; improved; in vivo; insight; joint injury; mitochondrial dysfunction; mouse development; normal aging; novel; novel strategies; novel therapeutic intervention; nutrient deprivation; overexpression; prevent; public health relevance; response

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）： 骨关节炎（OA）是最常见的关节疾病和残疾的主要原因。年龄和关节损伤是OA发展的主要风险因素。由于许多退伍军人年龄较大和/或在服役时有创伤性关节损伤，他们患OA的风险很高。然而，目前还没有有效的药物治疗来延迟和/或限制OA的发展和进展，这是一个迫切的医疗需求。 关节软骨进行性退变是本病的主要特征。软骨细胞是唯一存在于软骨中的细胞类型 基质，调节基质合成和降解之间的稳态平衡，这在OA中失败。因此，合理设计新OA疗法的一种方法是通过靶向疾病的发病机制来改善软骨细胞功能。 AMP活化蛋白激酶（AMPK）是能量稳态和细胞代谢的“超级调节剂”。我们最近发现，AMPK活性是组成性存在于正常的关节软骨细胞，但在OA软骨细胞减少，与增加的分解代谢反应。此外，软骨细胞中AMPK活性的丧失与炎症、生物力学损伤和衰老相关。此外，AMPK的药理学活化不仅减弱对炎性细胞因子和生物力学损伤的促分解代谢反应，而且促进线粒体生物合成并保护软骨细胞免受氧化应激。此外，在我们的初步体内研究中，我们观察到，小檗碱，一种用作传统药物和膳食补充剂的天然植物产品，并且已知激活AMPK，显著限制了小鼠由内侧半月板（DMM）手术失稳诱导的膝关节OA的发展。基于这些发现，我们建议测试我们的中心假设，即持续的AMPK活性对关节软骨稳态至关重要，AMPK是延迟和/或限制OA发作和进展的潜在干预靶点。 我们的具体目标是：（1）在分子水平上定义AMPK激活如何在体外具有软骨保护作用。(2)确定人类膝关节软骨中AMPK活性的降低，特别是在OA中软骨变性似乎开始的浅表区，是否是正常衰老的根本变化，为OA的发展和进展提供了平台。(3)测试AMPK活性的分子选择性丧失促进小鼠体内OA发展和进展的假设（4）使用STR/ort小鼠（类似于人OA的自发性OA的已建立模型）测试通过高选择性AMPK激活剂A-769662治疗性诱导AMPK活性延迟和/或限制自发性OA体内发展和进展的转化假设。 这些研究的完成将为软骨细胞生物能量学的变化如何影响软骨稳态提供新的见解，并有助于通过靶向AMPK来开发新的治疗方法，以抑制OA的发展和进展。