Department of Oral Implantology and Regenerative Dental Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
J Biomed Mater Res B Appl Biomater. 2010 Apr;93(1):65-73. doi: 10.1002/jbm.b.31559.
We have previously reported that healing of rat calvarial defects was enhanced by application of alpha tricalcium phosphate (alphaTCP) combined with simvastatin, a cholesterol synthesis inhibitor. The purpose of the present study was to investigate the cellular and molecular mechanisms in this phenomenon. Rat calvarial defects were grafted with alphaTCP with or without simvastatin or left untreated. Animals were sacrificed on 3, 7, 10, 14, and 21 days postoperatively and histological changes in the defect region were assessed. Gene expression patterns were examined by RT-PCR. Proliferation and migration of osteoprogenitor cells from the dura mater were increased in simvastatin group from day 3 to day 10 (p < 0.01). New bone formation was significantly increased in simvastatin group on day 14 and day 21 (p < 0.01). BMP-2 expression was significantly higher in simvastatin group on day 3 and day 14 (p < 0.05) and maintained until day 21. Increased upregulation of TGF-beta1 was also observed in the simvastatin group on day 7 (p < 0.05) which was maintained until day 14. These findings suggest that the proliferation and recruitment of osteoprogenitor cells were critical steps in early stage of bone healing and that these steps were enhanced by TGF-beta1 and BMP-2, which were stimulated by simvastatin.
我们之前曾报道过，将 alpha 磷酸三钙（alphaTCP）与胆固醇合成抑制剂辛伐他汀联合应用可增强大鼠颅骨缺损的愈合。本研究的目的是探讨这一现象的细胞和分子机制。将 alphaTCP 与或不与辛伐他汀联合应用于大鼠颅骨缺损，或不做任何处理。术后第 3、7、10、14 和 21 天处死动物，评估缺损区域的组织学变化。通过 RT-PCR 检查基因表达模式。从硬脑膜中分离的成骨前体细胞的增殖和迁移在辛伐他汀组从第 3 天到第 10 天增加（p < 0.01）。第 14 天和第 21 天，辛伐他汀组新骨形成明显增加（p < 0.01）。第 3 天和第 14 天，辛伐他汀组 BMP-2 的表达明显升高（p < 0.05），并持续至第 21 天。在辛伐他汀组中也观察到 TGF-β1 的上调增加，在第 7 天（p < 0.05），并持续至第 14 天。这些发现表明，成骨前体细胞的增殖和募集是骨愈合早期的关键步骤，而这些步骤通过 TGF-β1 和 BMP-2 增强，这两种物质被辛伐他汀刺激。
