Atorvastatin stimulates the production of osteoprotegerin by human osteoblasts
Atorvastatin stimulates the production of osteoprotegerin by human osteoblasts
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DOI：
10.1002/jcb.20598
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发表时间：
2005-12-15
影响因子：
4
通讯作者：
Hofbauer, LC
中科院分区：
文献类型：
--
作者：
Viereck, V;Gr端ndker, C;Hofbauer, LC
最近，HMG-CoA还原酶抑制剂（他汀类药物），胆固醇生物合成的有效抑制剂，已与骨代谢的保护作用有关。由于它们的广泛使用，预防骨质流失和骨折将是一个理想的副作用。然而，他汀类药物影响骨代谢的机制尚不明确。在这里，我们评估了阿托伐他汀对成骨细胞产生核因子κ B配体受体激活剂（RANKL）和骨保护素（OPG）的影响，这些细胞因子对破骨细胞生物学至关重要。而RANKL促进破骨细胞的形成和活化，从而；促进骨质流失，OPG作为可溶性诱饵受体并拮抗RANKL的作用。在原代人成骨细胞（hOB）中，阿托伐他汀以剂量依赖的方式使hOB的OPG mRNA水平和蛋白分泌增加3倍，在10(-6)M时效果最大（p < 0.001）。时间过程实验表明，阿托伐他汀对24 h后OPG mRNA水平和48-72 h后OPG蛋白分泌有时间依赖性的刺激作用（P < 0.001）。用HMG-CoA还原酶反应下游的胆固醇生物合成底物（甲羟戊酸、香叶基焦磷酸）处理hOB可逆转阿托伐他汀诱导的OPG生成增强。值得注意的是，阿托伐他汀消除了糖皮质激素对OPG产生的抑制作用。阿托伐他汀治疗hOB可增强成骨细胞分化标志物、碱性磷酸酶和骨钙素的表达。总之，我们的数据表明，阿托伐他汀可促进成骨细胞分化和OPG的产生。这可能有助于他汀类药物的保骨作用。j .细胞。生物化学学报，26(6):1244-1253,2005。(c) 2005 Wiley-Liss, Inc。
Recently, HMG-CoA reductase inhibitors (statins), potent inhibitors of cholesterol biosynthesis, have been linked to protective effects on bone metabolism. Because of their widespread use, prevention of bone loss and fractures would be a desirable side effect. However, the mechanisms how statins may affect bone metabolism are poorly defined. Here, we evaluated the effect of atorvastatin on osteoblastic production of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG), cytokines that are essential for osteoclast cell biology. While RANKL enhances osteoclast formation and activation, thereby; promoting bone loss, OPG acts as a soluble decoy receptor and antagonizes the effects of RANKL. In primary human osteoblasts (hOB), atorvastatin increased OPG mRNA levels and protein secretion by hOB by up to three fold in a dose-dependent manner with a maximum effect at 10(-6) M (p < 0.001). Time course experiments indicated a time-dependent stimulatory effect of atorvastatin on OPG mRNA levels after 24 h and on OPG protein secretion after 48-72 h (P < 0.001). Treatment of hOB with substrates of cholesterol biosynthesis that are downstream of the HMG-CoA reductase reaction (mevalonate, geranylgeranyl pyrophosphate) reversed atorvastatin-induced enhancement of OPG production. Of note, atorvastatin abrogated the inhibitory effect of glucocorticoids on OPG production. Treatment of hOB with atorvastatin enhanced the expression of osteoblastic differentiation markers, alkaline phosphatase and osteocalcin. In summary, our data suggest that atorvastatin enhances osteoblastic differentiation and production of OPG. This may contribute to the bone-sparing effects of statins. J. Cell. Biochem. 96: 1244-1253, 2005. (c) 2005 Wiley-Liss, Inc.