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11β-hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction

机译:11β-羟类固醇脱氢酶1型选择性抑制剂BVT.2733保护成骨细胞免受内源性糖皮质激素诱导的功能障碍

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References(26) Cited-By(5) Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11β-HSD1 was found increasingly expressed in bone with age. In spite of these obervations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11β-HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11β-HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11β-HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11β-HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11β-HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11β-HSD1, all of the above osteogenic repression effects by 11β-HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11β-HSD1 overexpression. These results demonstrated that the specific 11β-HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11β-HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11β-HSD1 can be a new therapeutic strategy for senile osteoporosis.
机译:参考文献(26)By-By(5)药理性糖皮质激素(GCs)抑制成骨细胞功能并诱发骨质疏松症。 1β-羟基类固醇脱氢酶1(11β-HSD1)可能在骨质疏松症中发挥作用,因为它通过将非活性GC转化为活性形式而在受体前水平上调节GC的作用。此外,发现11β-HSD1随着年龄的增长而在骨中表达增加。尽管有这些观察,其在老年性骨质疏松症中的功能仍不确定。在这项研究中,我们构建了一种过表达小鼠11β-HSD1的慢病毒载体,然后分别用阴性对照慢病毒和过表达11β-HSD1的慢病毒感染MC3T3-E1前成骨细胞。与被阴性对照慢病毒感染的细胞相比,在被11β-HSD1过表达慢病毒感染的MC3T3-E1细胞中,11β-HSD1的mRNA和蛋白质水平显着增加。在还原酶底物脱氢皮质酮(DHC)作用下,11β-HSD1过表达显着抑制了MC3T3-E1前成骨细胞的成骨分化。抑制作用类似于用过量GC抑制成骨作用,包括ALP活性,最终钙结节形成以及成骨基因(如ALP,BSP,OPN和OCN)的表达。但是,添加BVT.2733(一种11β-HSD1的选择性抑制剂)后,上述所有11β-HSD1过表达的成骨抑制作用均被逆转。此外,GC受体拮抗剂RU486也显示出相似的作用,防止11β-HSD1过表达抑制成骨作用。这些结果表明,特异的11β-HSD1抑制剂BVT.2733可以逆转11β-HSD1过表达的MC3T3-E1细胞对成骨分化的抑制作用。抑制11β-HSD1可能是老年性骨质疏松症的新治疗策略。

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