MECHANISMS OF CHONDROPROTECTION BY POMEGRANATE FRUIT EXTRACT

描述（由申请人提供）：骨关节炎（Osteoarthritis， OA）是美国和全世界老年人群中最常见的肌肉骨骼疾病。骨性关节炎的特征是手、膝、脊柱和臀部关节软骨的退变。虽然已经确定了导致OA发展的条件，但实际原因仍然未知。目前的治疗选择仅限于使用非甾体抗炎药（NSAIDs）缓解症状。由于与非甾体抗炎药治疗相关的并发症，草药提取物用于OA治疗的使用正在增加，但大多数这些药物作为膳食补充剂出售，其疗效和安全性尚未得到评估。石榴果（Punica granatum L）因其药用特性而备受推崇。石榴果或其提取物（PFE）被广泛应用于几种传统医学系统中，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。该实验室发表的研究表明，PFE对il - 1b诱导的p38-MAPK和JNK、NF-kB的激活以及体外人软骨外植体和软骨细胞中基质金属蛋白酶（MMPs）的表达具有有效的抑制作用。然而，其抑制分解代谢反应的机制尚不清楚。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）通过调节信号转导途径和转录因子的激活来抑制IL-1B的软骨降解作用，这些信号转导途径和转录因子会消极或积极地影响IL-1B诱导的与人软骨细胞分解代谢或合成代谢反应相关的基因的转录”。拟议的研究将确定PFE是否抑制MKK3和MKK6激酶（Specific Aim 1）；通过调节IkB上游激酶（NF-kB抑制剂）包括IKKa和IKKB的活化，抑制il - 1b诱导的NF-kB活化（Specific Aim 2）；PFE是否抑制il - 1b诱导的人软骨细胞氧化应激和去分化（Specific Aims 3,4）；并确定PFE的消耗是否会抑制软骨降解并抑制实验诱导的家兔OA的进展（Specific Aim 5）。我们的研究结果可能为使用PFE或其衍生化合物治疗和/或预防OA开辟了新的途径。

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.