Guanghua School of Stomatology, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, No. 56 Lingyuan West Road, Guangzhou, 510055, Guangdong, China.
Foshan Stomatological Hospital, School of Stomatology and Medicine, Foshan University, No. 5, Hebin Road, Chancheng District, Foshan, 528000, Guangdong, China.
Biol Direct. 2023 Jun 26;18(1):34. doi: 10.1186/s13062-023-00391-9.
Tooth development, as one of the major mineralized tissues in the body, require fine-tuning of mineralization micro-environment. The interaction between dental epithelium and mesenchyme plays a decisive role in this process. With epithelium-mesenchyme dissociation study, we found interesting expression pattern of insulin-like growth factor binding protein 3 (IGFBP3) in response to disruption of dental epithelium-mesenchyme interaction. Its action and related mechanisms as regulator of mineralization micro-environment during tooth development are investigated.
Expressions of osteogenic markers at early stage of tooth development are significantly lower than those at later stage. BMP2 treatment further confirmed a high mineralization micro-environment is disruptive at early stage, but beneficial at later stage of tooth development. In contrast, IGFBP3's expression increased gradually from E14.5, peaked at P5, and decreased afterwards, demonstrating an inverse correlation with osteogenic markers. RNA-Seq and Co-immunoprecipitation showed that IGFBP3 regulates the Wnt/beta-catenin signaling pathway activity by enhancing DKK1 expression and direct protein-protein interaction. The suppression of the mineralization microenvironment effectuated by IGFBP3 could be reversed by the DKK1 inhibitor WAY-262611, further demonstrating that IGFBP3 exerted its influence via DKK1.
A deeper understanding of tooth development mechanisms is essential for tooth regeneration, which have great implications for dental care. The current study demonstrated that the IGFBP3 expression is regulated in accordance with the needs of the mineralization microenvironment during tooth development, and IGFBP3 exerts its modulating action on osteogenic/odontogenic differentiation of hDPSCs by DKK1-Wnt/ beta-catenin axis.
牙齿发育是体内主要的矿化组织之一，需要精细调节矿化微环境。牙上皮和间充质的相互作用在这个过程中起着决定性的作用。通过上皮-间充质分离研究，我们发现胰岛素样生长因子结合蛋白 3（IGFBP3）在响应破坏牙上皮-间充质相互作用时表现出有趣的表达模式。研究了其作为牙齿发育过程中矿化微环境调节剂的作用及其相关机制。
牙齿发育早期的成骨标志物表达明显低于后期。BMP2 处理进一步证实，高矿化微环境在早期具有破坏性，但在牙齿发育后期是有益的。相比之下，IGFBP3 的表达从 E14.5 开始逐渐增加，在 P5 时达到峰值，随后下降，与成骨标志物呈负相关。RNA-Seq 和共免疫沉淀显示，IGFBP3 通过增强 DKK1 的表达和直接蛋白-蛋白相互作用来调节 Wnt/β-catenin 信号通路的活性。IGFBP3 抑制矿化微环境的作用可被 DKK1 抑制剂 WAY-262611 逆转，进一步表明 IGFBP3 通过 DKK1 发挥其影响。
深入了解牙齿发育机制对于牙齿再生至关重要，这对牙科护理具有重要意义。本研究表明，IGFBP3 的表达是根据牙齿发育过程中矿化微环境的需要进行调节的，IGFBP3 通过 DKK1-Wnt/β-catenin 轴对 hDPSCs 的成骨/成牙分化发挥调节作用。
