Department of Cariology and Endodontology, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China.
First Clinical Division, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing 100081, China.
Int J Mol Sci. 2024 Nov 11;25(22):12111. doi: 10.3390/ijms252212111.
Human periodontal ligament cells (hPDLCs) express matrix metalloproteinases (MMPs), a group of enzymes responsible for the destruction of most extracellular matrix proteins in dental tissues, especially MMP-1, MMP-2, and MMP-13. Exploring the regulatory mechanism of MMPs is crucial for understanding external root resorption (ERR), one of the most severe complications, along with substantial loss of dental tissue, induced by trauma, pulpal infection, tooth bleaching, and orthodontic treatment, etc. Discoidin domain receptor 1 (DDR1), a cell surface receptor binding to collagen, has the potential to regulate the expression of MMP-1, MMP-2, and MMP-13, but the mechanism remains unclear. Thus, the present study aimed to investigate the connection and underlying mechanism between MMP-1, MMP-2, MMP-13, and DDR1 in hPDLCs. Our post-replantation ERR model revealed that Mmp-1, Mmp-2, Mmp-13, and Ddr1 all increased in the sites of ERR. hPDLCs with DDR1 knockdown exhibited a substantial reduction in MMP-1, MMP-2, and MMP-13 expression. To further confirm the underlying mechanism, we conducted further in vitro experiments, including RNA sequencing, RNA interference, RT-qPCR, Western blotting, and ELISA. Based on our results, MMP-1 was positively regulated by the Smad2/3 and MEK-ERK1/2 pathways and negatively regulated by the PI3K-Akt pathway through CCN2. MMP-2 and MMP-13 were positively regulated by the Smad2/3 pathway. MMP-13 was positively regulated by the MEK-ERK1/2 and PI3K/Akt signaling pathways. Collectively, DDR1 is a potent regulator of MMP-1, MMP-2, and MMP-13 expression through the Smad2/3, MEK-ERK1/2, and PI3K/Akt signaling pathways. Clarifying the significance and underlying mechanism by which DDR1 is involved in ERR might bring the chances to hinder the pathogenic process of ERR, hence reducing its incidence rate.
人牙周韧带细胞（hPDLCs）表达基质金属蛋白酶（MMPs），这是一组负责破坏牙齿组织中大多数细胞外基质蛋白的酶，特别是 MMP-1、MMP-2 和 MMP-13。探索 MMPs 的调节机制对于理解外部根吸收（ERR）至关重要，ERR 是创伤、牙髓感染、牙齿漂白和正畸治疗等引起的最严重的并发症之一，同时还会导致大量牙齿组织丧失。盘状结构域受体 1（DDR1）是一种与胶原蛋白结合的细胞表面受体，有可能调节 MMP-1、MMP-2 和 MMP-13 的表达，但机制尚不清楚。因此，本研究旨在探讨 hPDLCs 中 MMP-1、MMP-2、MMP-13 和 DDR1 之间的联系和潜在机制。我们的再植后 ERR 模型显示，在 ERR 部位，Mmp-1、Mmp-2、Mmp-13 和 Ddr1 均增加。DDR1 敲低的 hPDLCs 中 MMP-1、MMP-2 和 MMP-13 的表达显著减少。为了进一步证实潜在机制，我们进行了进一步的体外实验，包括 RNA 测序、RNA 干扰、RT-qPCR、Western blot 和 ELISA。根据我们的结果，MMP-1 通过 CCN2 被 Smad2/3 和 MEK-ERK1/2 途径正向调节，被 PI3K-Akt 途径负向调节。MMP-2 和 MMP-13 受 Smad2/3 途径正向调节。MMP-13 受 MEK-ERK1/2 和 PI3K/Akt 信号通路正向调节。总之，DDR1 通过 Smad2/3、MEK-ERK1/2 和 PI3K/Akt 信号通路，成为 MMP-1、MMP-2 和 MMP-13 表达的有力调节剂。阐明 DDR1 参与 ERR 的意义和潜在机制，可能为阻止 ERR 发病过程提供机会，从而降低其发生率。
