Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Ann Rheum Dis. 2010 Dec;69(12):2189-98. doi: 10.1136/ard.2010.129197. Epub 2010 Aug 6.
To investigate if statins prevent cartilage degradation and the production of collagenases and gelatinases in bovine nasal and human articular cartilage after proinflammatory cytokine stimulation.
In a cartilage degradation model, the effects of several statins were assessed by measuring proteoglycan degradation and collagen degradation, while collagenolytic and gelatinolytic activity in culture supernatants were determined by collagen bioassay and gelatin zymography. The production of matrix metalloproteinases (MMPs) in cartilage and chondrocytes were analysed by real-time reverse transcriptase PCR and immunoassay. Cytokine-induced signalling pathway activation was studied by immunoblotting.
Simvastatin and mevastatin significantly inhibited interleukin 1 (IL-1)+oncostatin M (OSM)-induced collagen degradation; this was accompanied with a marked decrease in collagenase and gelatinase activity from bovine nasal cartilage. The cholesterol pathway intermediate mevalonic acid reversed the simvastatin-mediated protection of cartilage degradation, and the expression and production of collagenase (MMP-1 and MMP-13) and gelatinase (MMP-2 and MMP-9). Statins also significantly decreased MMP-1 and MMP-13 expression in human articular cartilage and chondrocytes stimulated with IL-1+OSM, and blocked the activation of critical proinflammatory signalling pathways required for MMP expression. The loss of the isoprenoid intermediate geranylgeranyl pyrophosphate due to statin treatment accounted for the inhibition of MMP expression and signalling pathway activation.
This study shows, for the first time, that lipophilic statins are able to block cartilage collagen breakdown induced by proinflammatory cytokines, by downregulating key cartilage-degrading enzymes. This demonstrates a possible therapeutic role for statins in acting as anti-inflammatory agents and in protecting cartilage from damage in joint diseases.
研究他汀类药物是否能在促炎细胞因子刺激后预防牛鼻和人关节软骨中的软骨降解以及胶原酶和明胶酶的产生。
在软骨降解模型中，通过测量蛋白聚糖降解和胶原降解来评估几种他汀类药物的作用，同时通过胶原生物测定法和明胶酶谱法测定培养上清液中的胶原酶和明胶酶活性。通过实时逆转录聚合酶链反应和免疫测定分析软骨和软骨细胞中基质金属蛋白酶（MMPs）的产生。通过免疫印迹研究细胞因子诱导的信号通路激活。
辛伐他汀和洛伐他汀显著抑制白细胞介素 1（IL-1）+骨形态发生蛋白 8（OSM）诱导的胶原降解；这伴随着牛鼻软骨胶原酶和明胶酶活性的显著降低。胆固醇途径中间产物甲羟戊酸逆转了辛伐他汀对软骨降解的保护作用，并降低了胶原酶（MMP-1 和 MMP-13）和明胶酶（MMP-2 和 MMP-9）的表达和产生。他汀类药物还显著降低了 IL-1+OSM 刺激的人关节软骨和软骨细胞中 MMP-1 和 MMP-13 的表达，并阻断了 MMP 表达和关键促炎信号通路的激活所必需的关键促炎信号通路的激活。由于他汀类药物治疗导致异戊烯基中间产物焦磷酸香叶酯的丧失，导致 MMP 表达和信号通路激活的抑制。
这项研究首次表明，亲脂性他汀类药物能够通过下调关键的软骨降解酶来阻止促炎细胞因子诱导的软骨胶原分解。这表明他汀类药物作为抗炎剂并保护关节疾病中的软骨免受损伤可能具有治疗作用。
