DPP promotes odontogenic differentiation of DPSCs through NF-κB signaling.
DPP promotes odontogenic differentiation of DPSCs through NF-κB signaling.
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DOI：
10.1038/s41598-021-01359-3
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发表时间：
2021-11-11
影响因子：
4.6
通讯作者：
George A
中科院分区：
文献类型：
--
作者：
Chen Y;Pethö A;Ganapathy A;George A
牙本质磷蛋白主要由成牙本质细胞合成和加工，具有结构蛋白和信号蛋白的双重功能。机制研究表明，DPP对DPSCs的刺激对DPSCs向功能性成牙本质细胞的分化有积极的影响。结果表明，κB信号转导和成牙本质细胞分化相关基因的转录激活受DPP信号的影响。具体地说，NF-κB的RelA/p65亚基被认为是启动分化级联反应的关键。共聚焦成像显示在DPP刺激下p65的核移位。芯片分析表明，核转录因子κB p65亚基与Runx2、Osx、Ocn、MMP1、MMP3、BMP4和PTX3启动子元件直接结合。用IKK-2的选择性抑制剂TPCA-1和阻止p65的核转位和κ结合的抑制剂JSH-23抑制NF-DNAB通路在分化过程中显示出损伤。茜素红染色的功能研究显示，在DPP刺激下，矿物质沉积旺盛，在抑制剂存在的情况下，矿物质沉积稀少，成牙本质细胞分化有缺陷。与野生型相比，DSPP基因缺失的小鼠在成牙本质细胞和牙髓细胞中表达的核因子-κB靶标OSX、OCN、PTX3和P65的表达水平较低。总体而言，这些结果表明，DPP介导的NF-κB激活在促进DPSCs分化的早期牙源性标志物的转录调控中发挥了重要作用。
Dentin phosphophoryn synthesized and processed predominantly by the odontoblasts, functions as both structural and signaling protein. Mechanistic studies revealed that DPP stimulation of DPSCs positively impacted the differentiation of DPSCs into functional odontoblasts. Results show that NF-κB signaling and transcriptional activation of genes involved in odontoblast differentiation were influenced by DPP signaling. Specifically, RelA/p65 subunit of NF-κB was identified as being responsible for the initiation of the differentiation cascade. Confocal imaging demonstrated the nuclear translocation of p65 with DPP stimulation. Moreover, direct binding of nuclear NF-κB p65 subunit to the promoter elements of Runx2, Osx, OCN, MMP1, MMP3, BMP4 and PTX3 were identified by ChIP analysis. Pharmacological inhibition of the NF-κB pathway using TPCA-1, a selective inhibitor of IKK-2 and JSH-23, an inhibitor that prevents nuclear translocation and DNA binding of p65 showed impairment in the differentiation process. Functional studies using Alizarin-Red staining showed robust mineral deposits with DPP stimulation and sparse deposition with defective odontoblast differentiation in the presence of inhibitors. In vivo expression of NF-κB targets such as OSX, OCN, PTX3 and p65 in odontoblasts and dental pulp cells from DSPP null mouse was lower when compared with the wild-type. Overall, the results suggest an important role for DPP-mediated NF-κB activation in the transcriptional regulation of early odontogenic markers that promote differentiation of DPSCs.
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