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

他汀类药物刺激 VEGF 基因转录分化成骨细胞的机制

• 批准号: 15591976
• 负责人: HORIUCHI Noboru
• 金额: $ 2.37万
• 依托单位: Ohu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591976/
• 关键词: Statins; MC3T3-E1 cells; Vascular endotherial growth factor (VEGF); BMP-2; prenylation; P13 kinase; Mineralization; Prenylation; statins; vascular endothelial growth factor (VEGF); hypoxia responsive elements (HRE); mineralization

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).

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 μ <-6>M）时间依赖性地增加MC 3 T3-E1细胞中VEGF mRNA的表达。VEGF启动子-荧光素酶构建体的转录激活通过辛伐他汀给药显著增加。结果表明辛伐他汀对VEGF基因的刺激本质上是转录的。他汀类药物通过减少蛋白质异戊二烯化和P13 K途径刺激成骨细胞中VEGF的表达，促进成骨细胞分化。我们研究了阿托伐他汀对卵巢切除（OVX）大鼠骨密度（BMD）的体内影响。阿托伐他汀（2 mg/kg）与17β-雌二醇（E_2）联合应用可显著增加腰椎（L2-L4）骨密度，与E_2或阿托伐他汀单用相比，差异有统计学意义（P &lt;0.05）。同时注射阿托伐他汀（2 mg/kg）和低剂量（1 mg/kg）的hPTH（1-34）可显著增强OVX大鼠腰椎的BMD。这些结果表明，阿托伐他汀长期给药似乎适度增加了用次大剂量E_2和hPTH（1-34）治疗的OVX大鼠腰椎的BMD。

项目成果

Tetsuya Kawane: "Parathyroid hormone (PTH) down-regulates PTH/PTH-related protein receptor gene expression in UMR-106 osteoblast-like cells via a 3',5'-cyclic adenosine monophosphate-dependent, protein kinase A-independent pathway."Journal of Endocrinolog

Tetsuya Kawane：“甲状旁腺激素 (PTH) 通过 3,5-环单磷酸腺苷依赖性、蛋白激酶 A 依赖性途径下调 UMR-106 成骨细胞样细胞中 PTH/PTH 相关蛋白受体基因的表达。

Leptin corrects increased gene expression of renal 25-hydroxyvitamin D3-1α-hydroxylase and -24-hydroxylase in leptin-deficient, ob/ob mice

• DOI: 10.1210/en.2003-1010
• 发表时间: 2004-03-01
• 期刊: ENDOCRINOLOGY
• 影响因子: 4.8
• 作者: Matsunuma, A;Kawane, T;Horiuchi, N
• 通讯作者: Horiuchi, N

Leptin corrects increased gene expression of renal 25-hydroxyvitamin D_3- lα-hydroxylase and -24-hydroxylase in leptin- deficient, ob/ob mice.

瘦素可纠正瘦素缺乏的 ob/ob 小鼠中肾脏 25-羟基维生素 D_3-1α-羟化酶和 -24-羟化酶基因表达的增加。

• 发表时间: 2004
• 期刊: Endocrinology 145-3
• 作者: Ayako Matsunuma;Tetsuya Kawane;Toyonobu Maeda;Setsuo Hamada;Noboru Horiuchi
• 通讯作者: Noboru Horiuchi

Effect of leptin on renal 1α-hydroxylase expression in mice.

瘦素对小鼠肾1α-羟化酶表达的影响。

• 发表时间: 2004
• 期刊: Proceedings of 12th International Congress of Endocrinology.
• 作者: Hamaguchi;H.;Fujimoto;K.;Kawamoto;T.;Noshiro;M.;Maemura;K.;Takeda;N.;Nagai;R.;Furukawa;M.;Honma;S.;Honma;K.;Kurihara;H.;Kato;Y;Noboru Horiuchi
• 通讯作者: Noboru Horiuchi

Suppression of parathyroid hormone-related protein expression by all trans-retinoic acid in human oral squamous carcinoma cells (HSC-3).

全反式视黄酸抑制人口腔鳞状细胞癌细胞 (HSC-3) 中甲状旁腺激素相关蛋白的表达。

• 发表时间: 2004
• 期刊: Journal of Oral Biosciences 46-6
• 作者: Masatoshi Abe;Nobutaka Haramoto;Hidefumi Itoh;Noboru Horiuchi.
• 通讯作者: Noboru Horiuchi.