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，也是导致残疾的主要原因。年龄和关节损伤是 OA 发展的主要危险因素之一。由于许多退伍军人年龄较大和/或在服役时遭受过外伤性关节损伤，因此他们患骨关节炎的风险很高。然而，目前还没有有效的医学疗法来延迟和/或限制 OA 的发生和进展，这是一个迫切的医疗需求。 关节软骨的进行性退化是该疾病的主要特征。软骨细胞，软骨中唯一的细胞类型 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，合理设计新的 OA 疗法的一种方法是通过针对疾病的发病机制来改善软骨细胞功能。 AMP 激活蛋白激酶 (AMPK) 是能量稳态和细胞代谢的“超级调节器”。我们最近发现 AMPK 活性基本存在于正常关节软骨细胞中，但在 OA 软骨细胞中降低，与分解代谢反应增加相关。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有关。此外，AMPK 的药理学激活不仅可以减弱对炎症细胞因子和生物力学损伤的促分解代谢反应，还可以促进线粒体生物发生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，已知可激活 AMPK）可显着限制小鼠因内侧半月板 (DMM) 手术不稳定而引起的膝骨关节炎的发展。基于这些发现，我们建议测试我们的中心假设，即持续的 AMPK 活性对于关节软骨稳态至关重要，并且 AMPK 是延迟和/或限制 OA 发病和进展的潜在干预靶点。 我们的具体目标是：(1) 定义 AMPK 激活如何在分子水平上发挥体外软骨保护作用。 (2) 确定人类膝关节软骨中 AMPK 活性的降低，特别是在 OA 中似乎开始软骨退变的浅表区域，是否是正常衰老的根本变化，为 OA 的发生和进展提供平台。 (3) 测试 AMPK 活性的分子选择性丧失促进小鼠体内 OA 发生和进展的假设 (4) 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 OA 发生和进展的翻译假设使用 STR/ort 小鼠（一种类似于人类 OA 的自发 OA 既定模型）体内自发性 OA 的发生和进展。 这些研究的完成将为软骨细胞生物能量的变化如何影响软骨稳态提供新的见解，并有助于开发一种新的治疗方法，通过靶向 AMPK 来抑制 OA 的发生和进展。