Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro
Inhibition of mevalonate pathway is involved in alendronate-induced cell growth inhibition, but not in cytokine secretion from macrophages in vitro
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DOI：
10.1016/s0928-0987(03)00108-8
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发表时间：
2003-07-01
影响因子：
4.6
通讯作者：
Mönkkönen, J
中科院分区：
文献类型：
--
作者：
Töyräs, A;Ollikainen, J;Mönkkönen, J
双膦酸盐是用于治疗代谢性骨疾病的抗骨吸收药物。它们可以分为两种不同的药理学类别：含氮和不含氮的双膦酸盐。不含氮的双膦酸盐，如氯膦酸盐，代谢为有毒的ATP类似物，防止破骨细胞介导的骨吸收。含氮二膦酸盐，包括阿仑膦酸盐，通过抑制甲羟戊酸途径阻止破骨细胞功能。已知氯膦酸盐具有抗炎特性，而阿仑膦酸盐诱导脂多糖（LPS）诱导的巨噬细胞分泌细胞因子。本研究探讨阿仑膦酸钠和LPS诱导的细胞毒性和细胞因子的产生是否可以抵消氯膦酸盐或甲羟戊酸途径的产物：氧化低密度脂蛋白（ox-LDL），法尼醇和香叶基香叶醇。用阿仑膦酸钠处理使LPS诱导的RAW 264巨噬细胞IL-1 β、IL-6和TNF-α的分泌分别增加2.4倍、1.4倍和1.8倍。该处理对巨噬细胞具有细胞毒性，如降低的细胞活力所示。Clodronate和ox-LDL都能抵消阿仑膦酸钠的细胞因子分泌和细胞毒性。法尼醇和香叶基香叶醇既不逆转细胞因子的分泌，也不降低阿仑膦酸钠的细胞毒性。氯膦酸盐和ox-LDL能够抵消阿仑膦酸盐对体外巨噬细胞的影响，可能是通过它们已知的抑制转录因子、核因子-κ B（NF-κ B）和活化蛋白-1（AP-1）的DNA结合活性的能力。这些结果表明，甲羟戊酸途径的抑制不是阿仑膦酸钠引起的促炎反应的机制，因为它是在阿仑膦酸钠诱导的细胞凋亡和破骨细胞功能的预防。(C)2003 Elsevier B. V.保留所有权利。
Bisphosphonates are antiresorptive drugs used for the treatment of metabolic bone diseases. They can be divided into two different pharmacological classes: nitrogen-containing and non-nitrogen-containing bisphosphonates. Non-nitrogen-containing bisphosphonates, like clodronate, are metabolised to a toxic ATP-analogue preventing osteoclast mediated bone resorption. Nitrogen-containing bisphosphonates, including alendronate, prevent osteoclast function by inhibiting the mevalonate pathway. Clodronate is known to have anti-inflammatory properties while alendronate induces cytokine secretion from lipopolysaccharide- (LPS) induced macrophages. This study investigates whether the cytotoxicity and cytokine production induced by alendronate and LPS could be counteracted by clodronate or products of mevalonate pathway: oxidized low density lipoprotein (ox-LDL), farnesol and geranylgeraniol. Treatment with alendronate increased LPS-induced secretion of IL-1beta, IL-6 and TNF-alpha from RAW 264 macrophages 2.4-, 1.4- and 1.8-fold, respectively. This treatment was cytotoxic for macrophages as indicated by lowered cell viability. Clodronate and ox-LDL both counteracted the cytokine secretion and cytotoxicity of alendronate. Farnesol and geranylgeraniol did neither reverse the cytokine secretion nor reduce the cytotoxicity of alendronate. Clodronate and ox-LDL were able to counteract the effects of alendronate on macrophages in vitro, probably by their known ability to inhibit DNA binding activity of transcription factors, nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1). These findings suggest that inhibition of mevalonate pathway is not the mechanism responsible for the proinflammatory response caused by alendronate, as it is in alendronate-induced apoptosis and prevention of osteoclast function. (C) 2003 Elsevier B.V. All rights reserved.