Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway.
Metformin combats high glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells via inhibition of the NPR3-mediated MAPK pathway.
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二甲双胍通过抑制NPR3介导的MAPK通路对抗高糖对人牙周膜干细胞成骨分化的损伤。
DOI：
10.1186/s13287-022-02992-z
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发表时间：
2022-07-15
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
长期以来，高糖对人牙周膜干细胞（PDLSCs）成骨分化的损伤一直是糖尿病患者牙周组织再生面临的挑战。二甲双胍是一种抗高血糖药物，具有丰富的与细胞代谢和下游组织再生相关的生物活性。然而，二甲双胍如何对抗高糖下PDLSC成骨分化的损伤及其潜在机制仍不清楚。通过碱性磷酸酶（ALP）染色、ALP活性、茜素红染色和定量分析、实时定量聚合酶链反应（qRT-PCR）和Western blot分析评估PDLSCs的成骨分化。通过RNA-seq分析筛选二甲双胍的靶基因，并通过慢病毒转染证实靶基因的作用。蛋白质印迹分析也用于检测潜在信号通路的蛋白质水平。我们发现，在高糖条件下，PDLSCs的成骨分化能力降低，二甲双胍的加入增强了这种分化能力。此外，RNA-seq分析的结果显示，在高糖下PDLSC中的利钠肽受体3（NPR 3）上调，并且在二甲双胍添加后下调。当研究所涉及的潜在途径时，我们发现NPR 3的上调可以损害二甲双胍增强的PDLSC成骨分化并激活MAPK途径（特别是p38 MAPK和Erk 1/2途径），并且NPR 3介导的p38 MAPK或Erk 1/2途径的抑制增强了高糖下PDLSC的成骨分化。本研究提示二甲双胍可能通过下调NPR 3及其下游MAPK通路促进高糖下PDLSCs的成骨分化。这是第一份鉴定NPR 3介导的MAPK通路参与二甲双胍增强的成骨分化的报告，表明NPR 3拮抗剂，如二甲双胍，可能是糖尿病个体牙周组织再生的可行治疗剂。在线版本包含补充材料，可通过10.1186/s13287-022-02992-z获得。
High glucose-induced damage to the osteogenic differentiation of human periodontal ligament stem cells (PDLSCs) has long been a challenge to periodontal regeneration for diabetic individuals. Metformin is an anti-hyperglycemic drug that exhibits abundant biological activities associated with cell metabolism and downstream tissue regeneration. However, how metformin combats damage to PDLSC osteogenic differentiation under high glucose and the underlying mechanisms remain unknown. Osteogenic differentiation of PDLSCs was assessed by alkaline phosphatase (ALP) staining, ALP activity, Alizarin Red staining and quantitative assay, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. RNA-seq analysis was performed to screen target genes of metformin, and the effects of target genes were confirmed using lentivirus transfection. Western blot analysis was also used to detect the protein level of underlying signaling pathways. We found that osteogenic differentiation of PDLSCs under high glucose was decreased, and metformin addition enhanced this capacity of differentiation. Furthermore, the results of RNA-seq analysis showed that natriuretic peptide receptor 3 (NPR3) was upregulated in PDLSCs under high glucose and downregulated after metformin addition. When the underlying pathways involved were investigated, we found that upregulation of NPR3 can compromise the metformin-enhanced PDLSC osteogenic differentiation and activate the MAPK pathway (especially the p38 MAPK and Erk1/2 pathway), and that inhibition of the NPR3-mediated p38 MAPK or Erk1/2 pathway enhanced the osteogenic differentiation of PDLSCs under high glucose. The present study suggests that metformin may enhance the osteogenic differentiation of PDLSCs under high glucose via downregulation of NPR3 and inhibition of its downstream MAPK pathway. This is the first report identifying the involvement of NPR3-mediated MAPK pathway in the metformin-enhanced osteogenic differentiation, indicating that NPR3 antagonists, such as metformin, may be feasible therapeutics for periodontal tissue regeneration in diabetic individuals. The online version contains supplementary material available at 10.1186/s13287-022-02992-z.
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