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。由于许多退伍军人在服役期间年龄较大和/或遭受创伤性关节损伤，因此他们有高风险开发OA。但是，目前尚无有效的医疗疗法来延迟和/或限制OA的开发和进展，这是紧迫的医疗需求。 关节软骨的进行性变性是该疾病的主要特征。软骨细胞，软骨中唯一的细胞类型 矩阵，调节矩阵合成与降解之间的稳态平衡，在OA中失败。因此，一种合理设计的新OA疗法的一种方法是通过靶向疾病的发病机理来改善软骨细胞功能。 AMP激活的蛋白激酶（AMPK）是能量稳态和细胞代谢的“超级调节剂”。我们最近发现，AMPK活性在正常的关节软骨细胞中存在组成性，但在OA软骨细胞中降低，与分解代谢反应的增加相关。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的药理学激活不仅减轻了对炎性细胞因子和生物力学损伤的促代谢反应，而且还促进了线粒体生物发生，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，berberine是一种自然植物产品，用作传统医学和饮食补充剂，并且已知为活跃的AMPK，这显着限制了小鼠的膝盖发育，该膝关节的发展是由外侧静an（DMM）的手术不稳定的。在这些发现的基础上，我们建议测试我们的中心假设，即持续的AMPK活动对于关节软骨稳态至关重要，并且AMPK是延迟和/或限制OA发作和进展的潜在介入目标。 我们专门针对以下目的：（1）定义AMPK激活在分子水平的体外软骨保护性如何。 （2）确定人膝关节软骨中的AMPK活性降低，尤其是在OA中似乎启动软骨变性的表面区域，是正常衰老的根本变化，为OA发育和进展提供了平台。 （3）检验以下假说：AMPK活性的分子选择性丧失促进体内小鼠的OA发展和进展（4）测试了翻译假说，即通过高度选择性AMPK激活剂A-7696662延迟和/或限制了Aner on on aan vivo oa in/note oa in-vivo（viivo in vivo in vivo in vivo in viivo）的治疗性诱导AMPK活性的治疗性诱导AMPK活性。 OA类似于人oa）。 这些研究的完成将为软骨细胞生物能力的变化如何影响软骨稳态提供新的见解，并通过针对AMPK靶向抑制OA的发展和进展，以开发新的治疗方法。