AMPK as an Interventional Target to Suppress the Development of Osteoarthritis

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。年龄和关节损伤是骨性关节炎发生的主要危险因素。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，他们患骨性关节炎的风险很高。然而，目前还没有有效的医学疗法来延缓和/或限制骨性关节炎的发展和进展，这是一种迫切的医学需求。关节软骨进行性退变是该病的主要特征。软骨细胞，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动态平衡，这在骨性关节炎中失败。因此，通过针对疾病的发病机制来改善软骨细胞功能是合理设计新的骨性关节炎治疗方法的途径之一。AMP活化蛋白激酶(AMPK)是能量稳态和细胞代谢的超级调节器。我们最近发现，AMPK活性在正常关节软骨细胞中存在，但在骨关节炎软骨细胞中降低，与分解代谢反应增加有关。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的药理激活不仅可以减弱对炎性细胞因子和生物力学损伤的促分解代谢反应，还可以促进线粒体的生物合成，保护软骨细胞免受氧化应激的影响。此外，在我们的初步体内研究中，我们观察到黄连素是一种用作传统药物和膳食补充剂的天然植物产品，已知具有AMPK活性，它显著限制了由手术引起的内侧半月板不稳定(DMM)导致的膝骨性关节炎的发生。基于这些发现，我们建议验证我们的中心假设，即持续的AMPK活性对于关节软骨的动态平衡至关重要，并且AMPK是一个潜在的干预靶点，可以延缓和/或限制OA的发生和发展。我们的具体目标是：(1)从分子水平确定AMPK的激活如何在体外发挥软骨保护作用。(2)确定人膝关节软骨中AMPK活性降低，特别是在软骨退变的浅表区是否为正常衰老的根本性改变，为骨关节炎的发生和发展提供平台。(3)验证AMPK活性的分子选择性丧失促进小鼠体内骨性关节炎发生发展的假说(4)检验翻译假说，即由高选择性的AMPK激活剂A-769662诱导的AMPK活性延迟和/或限制了STR/ORT小鼠(已建立的与人类骨性关节炎相似的自发性骨性关节炎模型)体内自发性骨性关节炎的发展和进展。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内稳态提供新的见解，并有助于通过靶向AMPK来开发新的治疗方法来抑制骨关节炎的发生和进展。

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.