Kaji H, Naito J, Inoue Y, Sowa H, Sugimoto T, Chihara K
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Horm Metab Res. 2008 Nov;40(11):746-51. doi: 10.1055/s-0028-1082051. Epub 2008 Jul 11.
Statins possess pleiotropic effects in several tissues. Among them, their bone anabolic actions have been recently noted. We have proposed that Smad3, a TGF-beta-signaling molecule, is a promoter of bone formation. However, whether statins would affect TGF-beta-Smad3 pathway in osteoblasts is still unknown. The present study was performed to examine the effects of statin on Smad3 expression and cell apoptosis by employing mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Statins (pitavastatin, mevastatin, and simvastatin) as well as alendronate increased the levels of Smad3 in MC3T3-E1 cells. The effects of pitavastatin on Smad3 levels were observed from 3 hours and later. Pitavastatin induced the expression of TGF-beta, and cycloheximide, a protein synthesis inhibitor, antagonized the increased levels of pitavastatin on Smad3. On the other hand, pitavastatin antagonized dexamethasone- or etoposide-induced apoptosis in a dose-dependent manner, and Smad3 inactivation by dominant negative Smad3 or an inhibition of endogenous TGF-beta action by SB431542 antagonized anti-apoptotic effects of pitavastatin, indicating that pitavastatin suppressed osteoblast apoptosis partly through TGF-beta-Smad3 pathway. In conclusion, the present study has demonstrated for the first time that statin suppressed cell apoptosis partly through TGF-beta-Smad3 pathway in osteoblastic cells.
他汀类药物在多个组织中具有多效性作用。其中，它们的骨合成代谢作用最近已被注意到。我们曾提出，Smad3，一种转化生长因子-β信号分子，是骨形成的促进因子。然而，他汀类药物是否会影响成骨细胞中的转化生长因子-β-Smad3信号通路仍不清楚。本研究通过使用小鼠成骨细胞MC3T3-E1和大鼠成骨细胞UMR-106细胞来检测他汀类药物对Smad3表达和细胞凋亡的影响。他汀类药物（匹伐他汀、美伐他汀和辛伐他汀）以及阿仑膦酸钠增加了MC3T3-E1细胞中Smad3的水平。匹伐他汀对Smad3水平的影响在3小时及之后即可观察到。匹伐他汀诱导了转化生长因子-β的表达，而蛋白质合成抑制剂环己酰亚胺拮抗了匹伐他汀对Smad3水平的升高作用。另一方面，匹伐他汀以剂量依赖的方式拮抗地塞米松或依托泊苷诱导的细胞凋亡，并且显性负性Smad3使Smad3失活或SB431542抑制内源性转化生长因子-β的作用拮抗了匹伐他汀的抗凋亡作用，表明匹伐他汀部分通过转化生长因子-β-Smad3信号通路抑制成骨细胞凋亡。总之，本研究首次证明他汀类药物部分通过转化生长因子-β-Smad3信号通路在成骨细胞中抑制细胞凋亡。
