Monjo Marta, Rubert Marina, Ellingsen Jan Eirik, Lyngstadaas S Petter
Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, Oslo, Norway.
Cell Physiol Biochem. 2010;26(4-5):647-56. doi: 10.1159/000322332. Epub 2010 Oct 29.
Rosuvastatin (RSV) is a synthetic statin with favourable pharmacologic properties including minimal metabolism, hepatic selectivity and enhanced inhibition of HMG-CoA reductase. An induction of osteoblast differentiation has been reported in vitro with lipophilic statins but not with RSV, which, like pravastatin, is relatively hydrophilic compared with other statins. To mediate its action, an active transport mechanism via solute carrier (SLC) transporters from the SLC16, SLC21/SLCO and SLC22 gene family - specifically Slc16a1, Slco1a1, Slco2b1 and Slc22a8 - may be present to allow effective entry in osteoblastic cells. In this study, we demonstrate that RSV induced osteoblast differentiation, as measured by increased BMP-2 gene expression and secretion, and ALP activity in MC3T3-E1 osteoblast cells, without significantly affecting cell proliferation within the concentration range of 0.001-10 μM. Low concentrations of RSV (0.001-0.01 μM) were protective against cell death whereas higher concentrations (10-100 μM) showed cytotoxicity. Moreover, MC3T3-E1 osteoblasts expressed high levels of Slco1a1 and Slc16a1 mRNA and low levels of Slco2b1 and Slc22a8 mRNA, when compared with kidney and liver tissues from mice. Slco1a1 gene expression increased 12-fold during osteoblast differentiation and was further regulated after RSV treatment. In conclusion, as for other statins, RSV promotes osteoblast differentiation, and also, demonstrated for the first time, regulates the expression of Slco1a1, which may constitute the transport system for RSV across the cell membrane in mature osteoblasts.
瑞舒伐他汀（RSV）是一种合成他汀类药物，具有良好的药理学特性，包括代谢极少、肝脏选择性以及对HMG-CoA还原酶的抑制作用增强。据报道，亲脂性他汀类药物在体外可诱导成骨细胞分化，但RSV却不能，与其他他汀类药物相比，RSV和普伐他汀一样相对亲水。为介导其作用，可能存在一种通过溶质载体（SLC）转运蛋白的主动转运机制，这些转运蛋白来自SLC16、SLC21/SLCO和SLC22基因家族——具体为Slc16a1、Slco1a1、Slco2b1和Slc22a8——以允许其有效进入成骨细胞。在本研究中，我们证明RSV可诱导成骨细胞分化，这通过MC3T3-E1成骨细胞中骨形态发生蛋白-2（BMP-2）基因表达和分泌增加以及碱性磷酸酶（ALP）活性来衡量，在0.001-10μM的浓度范围内，RSV对细胞增殖无显著影响。低浓度的RSV（0.001-0.01μM）可保护细胞免于死亡，而高浓度（10-100μM）则显示出细胞毒性。此外，与小鼠的肾脏和肝脏组织相比，MC3T3-E1成骨细胞中Slco1a1和Slc16a1 mRNA表达水平较高，而Slco2b1和Slc22a8 mRNA表达水平较低。Slco1a1基因表达在成骨细胞分化过程中增加了12倍，并且在RSV处理后受到进一步调节。总之，与其他他汀类药物一样，RSV促进成骨细胞分化，并且首次证明其调节Slco1a1的表达，这可能构成RSV在成熟成骨细胞中跨细胞膜的转运系统。
