ATP-Citrate Lyase As A Novel Metabolic Target for Osteoarthritis

衰老和肥胖是最常见的骨关节炎(OA)的主要危险因素 关节炎的一种形式。退伍军人患骨性关节炎的风险很高，因为超过1240万退伍军人的年龄在65岁或以上 年龄更大，而且近80%的退伍军人都很肥胖。对于退伍军人和其他人，开发有效的疾病修改 治疗骨性关节炎是一个尚未得到满足的主要医疗需求。随着骨性关节炎的进展，滑膜关节器官衰竭频繁。 发展，以关节软骨退变为核心疾病特征。软骨细胞，唯一的细胞 关节透明软骨，负责维持细胞外的动态平衡 基质合成代谢和分解代谢。局部炎症放大的骨性关节炎软骨细胞功能障碍 过程中，导致软骨细胞分解代谢活动过量，受包括一氧化氮在内的因素的影响 (NO)、基质金属蛋白酶(MMPs)和聚集聚糖酶。细胞新陈代谢可以与某些 表观遗传和转录因子修饰以调节细胞重新编程。三磷酸腺苷柠檬酸裂解酶(Acly) 是一种代谢酶，能将线粒体产生的柠檬酸转化为胞浆中的乙酰辅酶A， 细胞核，作为从头合成脂质和胞浆中蛋白质乙酰化的乙酰基供体， 核中组蛋白和转录因子的乙酰化，从而调节基因表达。我们的 初步研究表明，人膝关节骨性关节炎软骨细胞/软骨具有增强ACLY活性， 与组蛋白乙酰化增加有关。ACLY对骨性关节炎软骨细胞的药理抑制作用 通过调节血管紧张素转换酶的乙酰化来增加合成代谢和减少炎症介导的分解代谢活性 组蛋白和转录因子。基于这个翻译项目中的这些发现，我们建议测试我们的 中心假设软骨细胞ACLY是体内OA的可用药代谢靶点。我们将测试 假设(1)IL-1β和IGF-1激活Akt信号转导，这两个已知与 衰老和肥胖，在骨性关节炎软骨中表达上调，促使人类软骨细胞ACLY活性增加； (2)通过限制ACLY活性来保护软骨是通过增加软骨细胞的自噬来实现的； 抑制ACLY活性对肥胖诱导的骨性关节炎小鼠骨性关节炎的发生和发展具有保护作用 通过体内高脂饮食(HFD)和年龄相关的自发性骨性关节炎。这些研究的完成将提供新的 深入了解ACLY调节的代谢改变如何影响软骨组织的完整性，并可能提供 一种通过限制ACLY活性来抑制或延缓骨性关节炎发展和进展的新方法，尤其是 在那些因衰老和/或肥胖而风险增加的人中。

Aging and obesity are the major risk factors for development of osteoarthritis (OA), the most common form of arthritis. Veterans are at high risk of developing OA, because over 12.4 millions veterans are age 65 or older, and nearly 80% of veterans are obese. For veterans and others, developing effective disease-modifying therapy for OA is a major unmet medical need. As OA progresses, failure of the synovial joint organ frequently develops, with degeneration of articular cartilage as a core disease feature. Chondrocytes, the sole cells in articular hyaline cartilage, are responsible for maintaining the homeostatic balance between extracellular matrix anabolism and catabolism. Dysfunction of chondrocytes in OA, amplified by local inflammatory processes, leads to an excess of chondrocyte catabolic activity, medicated by factors including nitric oxide (NO), matrix metalloproteinasess (MMPs) and aggrecanases. Cellular metabolism can intersect with certain epigenetic and transcription factor modifications to mediate cellular re-programming. ATP citrate lyase (ACLY) is a metabolic enzyme that converts citrate generated from mitochondria to acetyl-CoA in the cytosol and nucleus, which serves as an acetyl donor for de novo lipid synthesis and acetylation of proteins in the cytosol, and acetylation of histones and transcription factors in the nucleus, thereby modulating gene expression. Our preliminary studies reveal that human knee OA chondrocytes/cartilages have increased ACLY activity, associated with increased acetylation of histones. Pharmacologic inhibition of ACLY in OA chondrocytes increases anabolic and decreases inflammation-mediated catabolic activities through modulating acetylation of histones and transcription factors. Building on these findings in this translational project, we propose to test our central hypothesis that chondrocyte ACLY is a druggable metabolic target for OA in vivo. We will test hypotheses that (1) activation of Akt signaling by IL-1β and IGF-1, both of which are known to associate with aging and obesity and are upregulated in OA cartilage, drives increased ACLY activity in human chondrocytes; (2) Chondroprotection by limiting ACLY activity is mediated by increased chondrocyte autophagy; (3) Suppression of ACLY activity protects mice from OA development and progression in both obesity-induced OA via high-fat diet (HFD) and age-related spontaneous OA in vivo. Completion of these studies will provide new insights into how metabolic alterations modulated by ACLY influence cartilage tissue integrity, and may provide a novel approach by limiting ACLY activity to suppress or delay OA development and progression, particularly in those at increased risk due to aging and/or obesity.