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首页> 外文期刊>Journal of cellular biochemistry. >Glucocorticoids inhibit notch target gene expression in osteoblasts
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Glucocorticoids inhibit notch target gene expression in osteoblasts

机译：糖皮质激素在成骨细胞中抑制陷波靶基因表达

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Abstract Glucocorticoids in excess suppress osteoblast function and cause osteoporosis. We demonstrated that cortisol induces the expression of selected Notch receptors in osteoblasts, revealing a potential mechanism for the skeletal effects of glucocorticoids. However, it remains to be determined whether increased expression of Notch receptors results into enhanced signaling. Following activation of Notch, its intracellular domain (NICD) binds to the DNA‐associated protein recombination signal binding protein for immunoglobulin kappa‐J region (RBPJ) and induces the expression of target genes such as Hey1 , Hey2 , and HeyL . To determine whether glucocorticoids modulate Notch signaling in the skeleton, 1 month old wild‐type mice were administered prednisolone or placebo and sacrificed after 72?h, and gene expression was analyzed in femoral bone. Prednisolone induced Tsc22d3 , a glucocorticoid target gene, and suppressed Hey1 and HeyL expression, which is indicative of inhibited Notch receptor activity or direct Hey downregulation. To determine the mechanisms of Hey suppression, wild‐type osteoblast‐enriched cells were seeded on the Notch cognate ligand Delta‐like (DLL)1 or transfected with constructs expressing the NOTCH1 NICD fragment and exposed to either cortisol or vehicle. Cortisol opposed the induction of mRNA and heterogeneous nuclear RNA for Hey1 , Hey2 , and HeyL by DLL1, but had no effect on mRNA stability, indicating that glucocorticoids inhibit Hey expression by transcriptional mechanisms. Transactivation studies and electrophoretic mobility shift assays revealed that cortisol did not oppose RBPJ‐mediated transcription or RBPJ/DNA interactions, respectively. In conclusion, glucocorticoids suppress expression of Hey1 , Hey2 , and HeyL in osteoblasts by RBPJ‐independent transcriptional mechanisms.
机译：摘要糖皮质激素在过度抑制骨赘功能和引起骨质疏松症。我们证明皮质醇诱导成骨细胞中所选凹口受体的表达，揭示糖皮质激素的骨骼效应的潜在机制。然而，它仍然确定陷波受体的表达是否导致增强的信号传导。在凹口激活后，其细胞内结构域（NICD）与用于免疫球蛋白Kappa-J区（RBPJ）的DNA相关蛋白质重组信号结合蛋白质结合，并诱导靶基因如Hey1，Hey2和Heyl的表达。为了确定糖皮质激素是否调节骨架中的凹口信号传导，将1个月大的野生型小鼠施用泼尼松或安慰剂，并在72℃后处死，并在股骨骨中分析基因表达。泼尼松酮诱导的TSC22D3，糖皮质激素靶基因和抑制的Hey1和赫基表达，其指示抑制缺口受体活性或直接嘿下调。为了确定γ抑制的机制，将野生型成骨细胞富集在凹口同源配体δ样（DLL）1上，或用表达Notch1 NiCd片段的构建体转染并暴露于皮质醇或载体。皮质醇反对通过DLL1诱导MRNA和异质核RNA，通过DLL1诱导HEY1，HEY2和Heyl，但对mRNA稳定性没有影响，表明糖皮质激素抑制母气通过转录机制抑制γ表达。反式激活研究和电泳迁移率移位测定显示皮质醇分别不反对RBPJ介导的转录或RBPJ / DNA相互作用。总之，糖皮质激素通过RBPJ无关的转录机制抑制了骨灌注物中HEY1，HEY2和Heyl的表达。

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