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

他汀类药物，如辛伐他汀，可抑制胆固醇合成。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^&lt；-6&gt；M)可时间依赖性地增强MC3T3-E1细胞中血管内皮生长因子的表达。辛伐他汀显著增加了血管内皮生长因子启动子-荧光素酶的转录激活。结果表明，辛伐他汀对血管内皮生长因子基因的刺激在本质上是转录的。他汀类药物通过减少蛋白预烯基化和P13K途径刺激成骨细胞表达血管内皮生长因子，促进成骨细胞分化。观察阿托伐他汀对去卵巢(OVX)大鼠骨密度的影响。联合应用阿托伐他汀(2 mg/kg)和17β-雌二醇(E_2)后，腰椎(L2-L4)骨密度明显高于单独应用E_2或阿托伐他汀。同时注射阿托伐他汀(2 mg/kg)和hPTH(1-34)，小剂量(1rig/kg)可显著提高去势大鼠腰椎骨密度。这些结果表明，长期服用阿托伐他汀似乎适度提高了次最大剂量E_2和hPTH(1-34)治疗的OVX大鼠的腰椎骨密度。

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).