Mechanism of osteoblast differantiation by statins via stimulation of VEGF gene transcription

他汀类药物如辛伐他汀抑制胆固醇合成。我们研究了他汀类药物对成骨细胞血管内皮生长因子（VEGF）表达的影响。辛伐他汀（10^<-6> M）时间依赖性增强MC3T3-E1细胞中VEGF mRNA的表达。使用辛伐他汀后，VEGF启动子-荧光素酶结构的转录激活显著增加。结果表明辛伐他汀对VEGF基因的刺激本质上是转录性的。他汀类药物通过降低蛋白烯酰化和P13K通路刺激成骨细胞中VEGF的表达，促进成骨细胞分化。研究了阿托伐他汀对去卵巢大鼠骨密度（BMD）的影响。阿托伐他汀（2 mg/kg）与17β-雌二醇（E_2）联合用药相比，E_2或阿托伐他汀单用可显著提高腰椎（L2-L4）的骨密度。低剂量（1 rig/kg）阿托伐他汀（2mg /kg）与hPTH（1-34）同时注射可显著提高OVX大鼠腰椎骨密度。这些发现表明，长期给药阿托伐他汀似乎可以适度地增强经次大剂量E_2和hPTH治疗的OVX大鼠腰椎的骨密度（1-34）。

Statins such as simvastatin inhibit cholesterol synthesis. We investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Simvastatin (10^<-6> M) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells. Transcriptional activation of a VEGF promoter - luciferase construct significantly increased by simvastatin administration. The results indicate that the stimulation of the VEGF gene by simvastatin is transcriptional in nature. Statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the P13K pathway, promoting osteoblastic differentiation. We investigated the in vivo effect of atorvastatin on bone mineral density (BMD) in ovariectomized (OVX) rats. The combination of atorvastatin (2 mg/kg) and 17β-estradiol (E_2) significantly enhanced the BMD of lumbar vertebrae (L2-L4) compared to that of either E_2 or atorvastatin alone. Concomitant injections of atorvastatin (2 mg/kg) with hPTH(1-34) at a low dose (1 rig/kg) significantly enhanced the BMD of lumbar vertebrae in OVX rats. These findings demonstrate that chronic administration of atorvastatin appears to modestly enhance the BMD of the lumbar vertebrae of OVX rats treated with submaximal doses of E_2 and hPTH( 1-34).