The chrondoprotective actions of a natural product are associated with the activation of IGF-1 production by human chondrocytes despite the presence of IL-1beta.
The chrondoprotective actions of a natural product are associated with the activation of IGF-1 production by human chondrocytes despite the presence of IL-1beta.
复制标题
DOI：
10.1186/1472-6882-6-13
复制
发表时间：
2006-04-07
影响因子：
--
通讯作者：
Haqqi, Tariq M
中科院分区：
文献类型：
--
作者：
Miller, Mark J S;Ahmed, Salahuddin;Haqqi, Tariq M
背景：软骨损失是关节炎的一个标志，是由于分解代谢过程的激活以及胰岛素样生长因子 1 (IGF-1) 等合成代谢途径的破坏而导致的。我们假设两种源自南美的天然产物将通过分别抑制分解代谢和激活局部 IGF-1 合成代谢途径来限制软骨退化。一种从猫爪草（Uncaria guianensis、vincaria）中提取的提取物是一种广为人知的 NF-kappaB 抑制剂。另一种提取物源自蔬菜 Lepidium meyenii (RNI 249)，其作用机制不确定，但在生育力和活力方面具有明确的民族医学应用。 方法：经同意从手术标本中获取人体软骨样品，并作为外植体或软骨基质酶消化后制备的原代软骨细胞进行评估。评估包括基础条件下和 IL-1beta 存在下的 IGF-1 基因表达、IGF-1 产生 (ELISA)、软骨基质降解和一氧化氮 (NO) 产生。结果：RNI 249 将人软骨细胞中的基础 IGF-1 mRNA 水平提高 2.7 倍，与长春花共同给药时，该效果进一步增强至 3.8 倍。在外植体和原代软骨细胞中均证实单独使用 RNI 249 以及与 Vincaria 一起使用可增强基础 IGF-1 的产生（P < 0.05）。正如预期的那样，IL-1β 暴露完全抑制了软骨细胞产生 IGF-1。然而，在存在 IL-1beta 的情况下，RNI 249 和 Vincaria 都以相加的方式保护 IGF-1 的产生 (P < 0.01)，并且组合将软骨细胞 IGF-1 的产生恢复到正常水平。 IL-1β 可显着增强软骨 NO 的产生。 Vincaria 和 RNI 249 都以相加的方式部分减弱 NO 的产生 (p < 0.05)。 IL-1β诱导的软骨基质降解被量化为糖胺聚糖释放。单独的 RNI 249 或 Vincaria 可以阻止 IL-1beta 的这种分解代谢作用。结论：即使面对 IL-1beta 等抑制性促炎、分解代谢细胞因子，鉴定出激活软骨中 IGF-1 自分泌产生的药物代表了一种新的软骨生物学治疗方法。这种天然产品与预防分解代谢事件相关的软骨保护作用以及持续合成代谢活性的潜力表明，它在治疗衰弱性关节疾病方面具有重大前景。
BACKGROUND: Cartilage loss is a hallmark of arthritis and follows activation of catabolic processes concomitant with a disruption of anabolic pathways like insulin-like growth factor 1 (IGF-1). We hypothesized that two natural products of South American origin, would limit cartilage degradation by respectively suppressing catabolism and activating local IGF-1 anabolic pathways. One extract, derived from cat's claw (Uncaria guianensis, vincaria), is a well-described inhibitor of NF-kappaB. The other extract, derived from the vegetable Lepidium meyenii (RNI 249), possessed an uncertain mechanism of action but with defined ethnomedical applications for fertility and vitality.METHODS: Human cartilage samples were procured from surgical specimens with consent, and were evaluated either as explants or as primary chondrocytes prepared after enzymatic digestion of cartilage matrix. Assessments included IGF-1 gene expression, IGF-1 production (ELISA), cartilage matrix degradation and nitric oxide (NO) production, under basal conditions and in the presence of IL-1beta.RESULTS: RNI 249 enhanced basal IGF-1 mRNA levels in human chondrocytes by 2.7 fold, an effect that was further enhanced to 3.8 fold by co-administration with vincaria. Enhanced basal IGF-1 production by RNI 249 alone and together with vincaria, was confirmed in both explants and in primary chondrocytes (P < 0.05). As expected, IL-1beta exposure completely silenced IGF-1 production by chondrocytes. However, in the presence of IL-1beta both RNI 249 and vincaria protected IGF-1 production in an additive manner (P < 0.01) with the combination restoring chondrocyte IGF-1 production to normal levels. Cartilage NO production was dramatically enhanced by IL-1beta. Both vincaria and RNI 249 partially attenuated NO production in an additive manner (p < 0.05). IL-1beta - induced degradation of cartilage matrix was quantified as glycosaminoglycan release. Individually RNI 249 or vincaria, prevented this catabolic action of IL-1beta.CONCLUSION: The identification of agents that activate the autocrine production of IGF-1 in cartilage, even in the face of suppressive pro-inflammatory, catabolic cytokines like IL-1beta, represents a novel therapeutic approach to cartilage biology. Chondroprotection associated with prevention of the catabolic events and the potential for sustained anabolic activity with this natural product suggests that it holds significant promise in the treatment of debilitating joint diseases.