Statin-induced calcification in human mesenchymal stem cells is cell death related.
Statin-induced calcification in human mesenchymal stem cells is cell death related.
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DOI：
10.1111/j.1582-4934.2008.00545.x
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发表时间：
2009-11
影响因子：
5.3
通讯作者：
Alini M
中科院分区：
文献类型：
--
作者：
Kupcsik L;Meurya T;Flury M;Stoddart M;Alini M
他汀类药物被广泛用于临床降低胆固醇水平。最近，它们已被证明对大鼠模型中的骨形成和骨量有积极影响。本研究旨在探讨普伐他汀、辛伐他汀和洛伐他汀对体外培养的人骨髓间充质干细胞（MSCs）向成骨细胞分化的影响。测定细胞数量、碱性磷酸酶（ALP）活性、基质矿化和基因表达模式。普伐他汀不影响细胞分化。辛伐他汀和洛伐他汀增强骨形态发生蛋白2（BMP-2）mRNA水平。与此相反，ALP活性和mRNA水平抑制他汀类药物，以及DNA含量和细胞活性（MTT）。在高浓度他汀类药物下观察到凋亡事件增加，沿着高Ca-45掺入。较低浓度的他汀类药物没有增加凋亡染色，但也未能诱导钙化。当他汀类药物诱导的钙化确实发生时，沉积物的形态与常规结节形成非常不同;钙沿着圆形细胞的膜沉积，表明这是细胞死亡的结果。我们的研究结果表明，他汀类药物不能使人MSC分化为成骨细胞，高浓度的他汀类药物（>1 μM）具有细胞毒性作用。
Statins are widely used in clinics to lower cholesterol levels. Recently, they have been shown to positively affect bone formation and bone mass in a rat model. The aim of this study was to investigate the effect of pravastatin, simvastatin and lovastatin on the osteoblastic differentiation of human mesenchymal stem cells (MSCs) in vitro. Cell number, alkaline phosphatase (ALP) activity, matrix mineralization and gene expression pattern were determined. Pravastatin did not affect cell differentiation. Simvastatin and lovastatin enhanced bone morphogenetic protein 2 (BMP-2) mRNA levels. In contrast, ALP activity and mRNA levels were suppressed by statins, as well as the DNA content and cell activity (MTT). An increase in apoptotic events was observed at high concentrations of statins, along with high Ca-45 incorporation. Lower concentrations of statins did not increase apoptotic staining, but also failed to induce calcification. When statin-induced calcification did occur, the morphology of the deposits was very different from the conventional nodule formation; the calcium was laid down along the membranes of the rounded cells suggesting it was as a result of cell death. Our results indicate that statins are not able to differentiate human MSCs into osteoblasts and that high concentrations of statins (>1 μM) have a cytotoxic effect.