MECHANISMS OF CHONDROPROTECTION BY POMEGRANATE FRUIT EXTRACT

描述(申请人提供)：骨关节炎(OA)是美国和世界各地老年人口中最常见的肌肉骨骼疾病。骨性关节炎的特征是手、膝、脊柱和髋关节的关节软骨退变。虽然已经确定了促进开放式学习发展的条件，但实际原因仍不清楚。目前的治疗选择仅限于使用非类固醇抗炎药(NSAIDs)缓解症状。由于与非类固醇抗炎药治疗相关的并发症，用于治疗骨性关节炎的草药提取物的使用正在增加，但这些作为膳食补充剂出售的大多数药物尚未对其有效性和安全性进行评估。石榴果实(石榴L)因其药用价值而历来受到推崇。石榴果实或其提取物(PFE)被广泛用于几种传统医药系统，用于治疗关节炎和其他疾病的炎症和疼痛。石榴果实(PF)的可食用部分富含花青素，这是一组具有抗氧化和抗炎活性的多酚化合物。本实验室已发表的工作表明，PFE在体外对IL-1B诱导的人软骨外植体和软骨细胞p38-MAPK和JNK、NF-kB的激活以及基质金属蛋白酶(MMPs)的表达具有明显的抑制作用。然而，抑制分解代谢反应的机制仍不清楚。根据我们已发表的和初步的研究，我们假设“石榴果提取物(PFE)通过调节信号转导通路和转录因子的激活来抑制IL-1B的软骨降解作用，这些信号转导通路和转录因子对IL-1B诱导的人软骨细胞分解代谢或合成代谢相关基因的转录产生负面或正面影响”。拟议的研究将确定PFE是否抑制MKK3和MKK6激酶(特定目标1)；通过调节包括Ikka和IKKB在内的IKB(核因子-kB抑制物)上游激酶的激活来抑制IL-1B诱导的NF-kB的激活(特定目标2)；PFE是否抑制IL-1B诱导的人软骨细胞的氧化应激和去分化(特定目标3、4)；以及确定“PFE的消费是否会抑制软骨降解和抑制实验性诱导的兔骨关节炎的进展(特定目标5)。我们的发现可能为使用PFE或其衍生的化合物治疗和/或预防骨性关节炎开辟新的途径。

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common musculoskeletal disease among the aging population in the United States and throughout the world. OA is characterized by degeneration of articular cartilage of the joints in hands, knees, spine and hips. While conditions predisposing to the development of OA have been identified the actual causes remain unknown. The current treatment options are limited to relief of symptoms using nonsteroidal anti-inflammatory drugs (NSAIDs). Due to complications associated with NSAIDs therapy, the use of herbal extracts for the treatment of OA is on the rise but most of these agents, sold as dietary supplements, have not been evaluated for their efficacy and safety. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit or its extract (PFE) is widely used in several traditional medicinal systems for the treatment of inflammation and pain in arthritis and other diseases. Edible part of pomegranate fruit (PF) is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Published work from this laboratory has shown that PFE exert a potent inhibitory effect on IL-1B-induced activation of p38-MAPK and JNK, NF-kB and expression of matrix metalloproteinases (MMPs) by human cartilage explants and chondrocytes in vitro. However, the mechanism of the inhibition of catabolic response remains elusive. Based on our published and preliminary studies we hypothesize that "pomegranate fruit extract (PFE) inhibit the cartilage degrading effects of IL-1B by regulating the activation of signal transduction pathways and transcription factors which negatively or positively affect the IL-1B-induced transcription of genes associated with the catabolic or anabolic response in human chondrocytes". Proposed studies will determine whether PFE inhibit the MKK3 and MKK6 kinases(Specific Aim 1); inhibit the IL-1B-induced activation of NF-kB by modulating the activation of kinases upstream of IkB (inhibitor of NF-kB) including IKKa and IKKB (Specific Aim 2); whether PFE inhibit the IL-1B-induced oxidative stress and dedifferentiation of human chondrocytes (Specific Aims 3, 4); and determine whether "consumption of PFE will inhibit the cartilage degradation and suppress the progression of experimentally induced OA in rabbits (Specific Aim 5). Our findings may open new avenues regarding the use of PFE or compounds derived from it for the treatment and/or prevention of OA.