Mechanisms of Chondroprotection by Pomegranate Fruit Extract

骨关节炎（OA）是美国老年人中最常见的肌肉骨骼疾病 国家和世界各地。OA的特征是关节软骨的退化， 手、膝盖、脊柱和臀部。虽然诱发OA发展的条件已被确定， 真正的原因仍然不明。目前的治疗选择仅限于使用 非甾体抗炎药（NSAID）。由于与NSAID治疗相关的并发症， 用于治疗OA的草药提取物的使用正在增加，但这些药剂中的大多数，作为膳食补充剂出售， 尚未对其有效性和安全性进行评估。石榴（Punica granatum L） 一直以来都有药用价值菠萝果或其提取物（PFE）广泛用于几种 用于治疗关节炎和其他疾病中的炎症和疼痛的传统医学系统。食用 石榴果实的一部分富含花青素，花青素是一组多酚类化合物， 抗氧化和抗炎活性。该实验室已发表的工作表明，PFE发挥了 对IL-1B诱导的p38-MAPK和JNK、NF-kB活化及基质表达的有效抑制作用 体外培养人软骨组织和软骨细胞，观察其对基质金属蛋白酶（MMPs）的影响。然而，机制 分解代谢反应的抑制仍然是难以捉摸的。根据我们发表的和初步的研究， 假设“石榴果实提取物（PFE）通过调节IL-1 β抑制软骨降解作用， 信号转导通路和转录因子的激活，其负面或正面影响 IL-1-β诱导的人分解代谢或合成代谢相关基因转录 软骨细胞”。拟议的研究将确定PFE是否抑制MKK 3和MKK 6激酶（特异性 目的1）通过调节kB上游激酶的活化来抑制IL-1 β诱导的NF-κ B活化 （NF-κ B的抑制剂），包括IKKa和IKK（3）（特异性目的2）; PFE是否抑制IL-1（3-诱导的氧化性 人软骨细胞应激和去分化（具体目的3，4）;并确定是否“消耗 PFE将抑制软骨降解并抑制实验诱导的OA的进展， 兔（具体目标5）。我们的研究结果可能会开辟新的途径，关于使用PFE或衍生化合物， 用于治疗和/或预防OA。

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-IB-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-1 (3 by regulating the activation of signal transduction pathways and transcription factors which negatively or positively affect the IL1-(3 -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-1p-induced activation of NF-KB by modulating the activation of kinases upstream of kB (inhibitor of NF-KB) including IKKa and IKK(3 (Specific Aim 2); whether PFE inhibit the IL-1(3-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.