The role of tumor necrosis factor alpha in down-regulation of osteoblast Phex gene expression in experimental murine colitis.
The role of tumor necrosis factor alpha in down-regulation of osteoblast Phex gene expression in experimental murine colitis.
复制标题
肿瘤坏死因子α在实验性小鼠结肠炎成骨细胞Phex基因表达下调中的作用。
DOI：
10.1053/j.gastro.2006.05.020
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发表时间：
2006
期刊：
影响因子：
29.4
通讯作者：
Ghishan,FayezK
中科院分区：
文献类型：
--
作者：
Uno,JenniferK;Kolek,OlgaI;Hines,EricR;Xu,Hua;Timmermann,BarbaraN;Kiela,PawelR;Ghishan,FayezK
背景与目的骨量减少是炎症性肠病（IBD）的常见并发症，尽管导致骨质减少的机制尚不完全清楚。肿瘤坏死因子α (TNF-α)在IBD患者中上调，对成骨细胞有不利影响。Phex基因主要在成骨细胞中表达，其破坏导致骨矿化缺陷。本研究的目的是评估TNF-α是否调节Phex基因表达从而导致IBD中观察到的骨代谢异常。方法用三硝基苯磺酸（TNBS）加或不加中和抗TNF-α抗体、膳食姜黄素或全身注射重组TNF-α，观察sphex基因在6 - 7周龄小鼠颅骨中的表达。TNF-α处理的UMR-106成骨细胞也被检测。在瞬时转染TNF-α -处理的UMR-106细胞中检测Phex启动子活性。结果与对照组相比，TNBS结肠炎小鼠和TNF-α注射小鼠的Phex信使RNA （mRNA）表达降低40% ~ 50%。饲粮中添加姜黄素和抗tnf -α抗体可抵消TNBS对Phex基因表达的不利影响。TNF-α处理的UMR-106细胞显示出浓度依赖性和转录介导的Phex mRNA和基因启动子活性降低，Phex启动子的- 133至- 74 bp区域可能参与了TNF-α作用的机制。与Phex蛋白水平降低一致，TNF-α显著降低UMR-106成骨细胞的矿化。结论急性结肠炎和TNF-α通过转录机制降低Phex mRNA和蛋白的表达。TNF-α -介导的Phex蛋白的减少至少在一定程度上抑制了成骨细胞矿化，并且所描述的机制可能导致与IBD相关的骨代谢异常。
Background & AimsReduced bone mass is a common complication of inflammatory bowel disease (IBD), although the mechanisms that contribute to osteopenia are not completely understood. Tumor necrosis factor α (TNF-α) is up-regulated in patients with IBD and has detrimental effects on osteoblasts. Phex gene is expressed predominantly in osteoblasts, and its disruption results in defective bone mineralization. The aim of this study was to evaluate whether TNF-α regulates Phex gene expression thus contributing to the abnormal bone metabolism observed in IBD.MethodsPhex gene expression was evaluated in calvaria of 6–7-week-old mice administered with trinitrobenzene sulfonic acid (TNBS) with or without neutralizing anti–TNF-α antibody, dietary curcumin, or systemically with recombinant TNF-α. TNF-α–treated UMR-106 osteoblasts were also examined. Phex promoter activity was assayed in transiently transfected TNF-α–treated UMR-106 cells.ResultsCompared with control animals, Phex messenger RNA (mRNA) expression decreased by 40%–50% in both TNBS colitis and TNF-α–injected mice. Dietary curcumin and anti–TNF-α antibody counteracted the detrimental effect of TNBS on Phex gene expression. TNF-α–treated UMR-106 cells showed a concentration-dependent and transcriptionally mediated decrease in Phex mRNA and gene promoter activity, with the −133 to −74 bp region of the Phex promoter likely involved in the mechanism of TNF-α action. Coinciding with decreased Phex protein level, TNF-α drastically reduced mineralization in UMR-106 osteoblasts.ConclusionsAcute colitis and TNF-α decrease Phex mRNA and protein expression via a transcriptional mechanism. TNF-α–mediated reduction in Phex protein is at least in part responsible for inhibition of osteoblast mineralization, and the described mechanism may contribute to the abnormal bone metabolism associated with IBD.