Osteoblasts and osteoclasts play essential and opposite roles in maintaining bone homeostasis. Osteoblasts fill cavities excavated by osteoclasts. The mevalonate pathway provides essential prenyl pyrophosphates for the activities of GTPases that promote differentiation of osteoclasts but suppress that of osteoblasts. Preclinical and clinical studies suggest that mevalonate suppressors such as statins increase bone mineral density and reduce risk of bone fracture. Tocotrienols down-regulate 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway. In vivo studies have shown the bone-protective activity of tocotrienols. We hypothesize that d-δ-tocotrienol, a mevalonate suppressor, induces differentiation of murine MC3T3-E1 preosteoblasts. Alizarin staining showed that d-δ-tocotrienol (0-25 μmol/L) induced mineralized nodule formation in a concentration-dependent manner in MC3T3-E1 preosteoblasts. d-δ-Tocotrienol (0-25 μmol/L), but not D-α-tocopherol (25 μmol/L), significantly induced alkaline phosphatase activity, an indicator of preosteoblast differentiation. The expression of differentiation marker genes including BMP-2 and VEGFα was stimulated dose dependently by d-δ-tocotrienol (0-25 μmol/L). Concomitantly, Western blot analysis showed that d-δ-tocotrienol down-regulated HMG CoA reductase. d-δ-Tocotrienol (0-25 μmol/L) had no impact on the viability of MC3T3-E1 preosteoblasts following 48-h incubation, suggesting lack of cytotoxicity at these doses. Tocotrienols and other mevalonate suppressors have potential in maintaining bone health.

中文翻译：

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d-δ-生育三烯酚对小鼠 MC3T3-E1 前成骨细胞分化的刺激作用。

成骨细胞和破骨细胞在维持骨稳态中起着重要而相反的作用。成骨细胞填充破骨细胞挖出的空腔。甲羟戊酸途径为促进破骨细胞分化但抑制成骨细胞分化的 GTP 酶的活性提供必需的异戊二烯焦磷酸盐。临床前和临床研究表明，他汀类药物等甲羟戊酸抑制剂可增加骨矿物质密度并降低骨折风险。生育三烯酚下调 3-羟基-3-甲基戊二酰辅酶 A (HMG CoA) 还原酶，这是甲羟戊酸途径中的限速酶。体内研究表明生育三烯酚具有骨保护活性。我们假设 d-δ-生育三烯酚（一种甲羟戊酸抑制剂）诱导小鼠 MC3T3-E1 前成骨细胞分化。茜素染色显示 d-δ-生育三烯酚 (0-25 μmol/L) 在 MC3T3-E1 前成骨细胞中以浓度依赖性方式诱导矿化结节形成。d-δ-生育三烯酚 (0-25 μmol/L)，而不是 D-α-生育酚 (25 μmol/L)，显着诱导碱性磷酸酶活性，这是前成骨细胞分化的指标。d-δ-生育三烯酚（0-25 μmol/L）以剂量依赖性方式刺激包括BMP-2和VEGFα在内的分化标志基因的表达。同时，Western 印迹分析显示 d-δ-生育三烯酚下调 HMG CoA 还原酶。d-δ-生育三烯酚 (0-25 μmol/L) 在孵育 48 小时后对 MC3T3-E1 前成骨细胞的活力没有影响，表明在这些剂量下没有细胞毒性。生育三烯酚和其他甲羟戊酸抑制剂具有维持骨骼健康的潜力。