Osteogenic oxysterol, 20(S)-hydroxycholesterol, induces notch target gene expression in bone marrow stromal cells.
Osteogenic oxysterol, 20(S)-hydroxycholesterol, induces notch target gene expression in bone marrow stromal cells.
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DOI：
10.1359/jbmr.091024
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Parhami F
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文献类型：
--
作者：
Kim WK;Meliton V;Tetradis S;Weinmaster G;Hahn TJ;Carlson M;Nelson SF;Parhami F
我们以前报道过，特定的氧固醇刺激多能骨髓基质细胞（MSC）的成骨分化，通过激活刺猬（Hh）信号，并可能作为潜在的未来治疗干预骨质疏松症和骨质疏松症。在这项研究中，我们报告了成骨氧化固醇20（S）-羟基胆固醇（20 S）诱导与Notch信号相关的基因表达。使用M2- 10 B4（M2）MSC，我们发现与未处理的细胞相比，20 S显著诱导HES-1，HEY-1和HEY-2 mRNA表达，48小时后诱导最大，而非成骨氧化固醇则没有。当用音刺猬（Shh）处理M2细胞时，也出现了类似的观察结果，并且特异性Hh途径抑制剂环巴胺阻断了20 S诱导的Notch靶基因表达。20 S在Smo−/−小鼠胚胎成纤维细胞中没有诱导Notch靶基因，进一步证实了Hh信号在20 S诱导的Notch靶基因表达中的作用。尽管肝脏X受体（LXR）合成配体TO 901317不能诱导M2细胞中的Notch靶基因，但使用siRNA进行的LXR敲除研究显示，20 S诱导的HEY-1表达受到抑制，但HES-1表达没有受到抑制，这表明LXR信号传导在MSC对20 S的反应中发挥了部分作用。此外，20 S诱导的Notch靶基因表达不依赖于经典Notch信号传导，因为20 S和Shh均不诱导CBF 1荧光素酶报告基因活性或NICD蛋白在细胞核中的积累，这是经典Notch信号传导激活的标志。最后，HES-1和HEY-1 siRNA转染显著抑制20 S诱导的成骨基因，表明20 S的促成骨作用部分受HES-1和HEY-1调节。© 2010美国骨与矿物质研究学会
We previously reported that specific oxysterols stimulate osteogenic differentiation of pluripotent bone marrow stromal cells (MSCs) through activation of hedgehog (Hh) signaling and may serve as potential future therapies for intervention in osteopenia and osteoporosis. In this study we report that the osteogenic oxysterol 20(S)-hydroxycholesterol (20S) induces the expression of genes associated with Notch signaling. Using M2-10B4 (M2) MSCs, we found that 20S significantly induced HES-1, HEY-1, and HEY-2 mRNA expression compared with untreated cells, with maximal induction after 48 hours, whereas the nonosteogenic oxysterols did not. Similar observations were made when M2 cells were treated with sonic hedgehog (Shh), and the specific Hh pathway inhibitor cyclopamine blocked 20S-induced Notch target gene expression. 20S did not induce Notch target genes in Smo−/− mouse embryonic fibroblasts, further confirming the role of Hh signaling in 20S-induced expression of Notch target genes. Despite the inability of liver X-receptor (LXR) synthetic ligand TO901317 to induce Notch target genes in M2 cells, LXR knockdown studies using siRNA showed inhibition of 20S-induced HEY-1 but not HES-1 expression, suggesting the partial role of LXR signaling in MSC responses to 20S. Moreover, 20S-induced Notch target gene expression was independent of canonical Notch signaling because neither 20S nor Shh induced CBF1 luciferase reporter activity or NICD protein accumulation in the nucleus, which are hallmarks of canonical Notch signaling activation. Finally, HES-1 and HEY-1 siRNA transfection significantly inhibited 20S-induced osteogenic genes, suggesting that the pro-osteogenic effects of 20S are regulated in part by HES-1 and HEY-1. © 2010 American Society for Bone and Mineral Research
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DOI：
10.1083/jcb.200609014
发表时间：
2007-02-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nichols JT;Miyamoto A;Olsen SL;D'Souza B;Yao C;Weinmaster G
通讯作者：
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影响因子：
6.5
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影响因子：
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影响因子：
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