Lee Eui-Seon, Aryal Yam Prasad, Kim Tae-Young, Pokharel Elina, Kim Ji-Youn, Yamamoto Hitoshi, An Chang-Hyeon, An Seo-Young, Jung Jae-Kwang, Lee Youngkyun, Ha Jung-Hong, Sohn Wern-Joo, Kim Jae-Young
Department of Biochemistry, Daegu, South Korea.
Department of Dental Hygiene, Gachon University, Incheon, Korea.
Front Physiol. 2023 Jan 4;13:1079355. doi: 10.3389/fphys.2022.1079355. eCollection 2022.
During tooth development, proper protein folding and trafficking are significant processes as newly synthesized proteins proceed to form designated tissues. Endoplasmic reticulum (ER) stress occurs inevitably in tooth development as unfolded and misfolded proteins accumulate in ER. 4-Phenylbutyric acid (4PBA) is a FDA approved drug and known as a chemical chaperone which alleviates the ER stress. Recently, several studies showed that 4PBA performs therapeutic effects in some genetic diseases due to misfolding of proteins, metabolic related-diseases and apoptosis due to ER stress. However, the roles of 4PBA during odontogenesis are not elucidated. This study revealed the effects of 4PBA during molar development in mice. We employed in vitro organ cultivation and renal transplantation methods which would mimic the permanent tooth development in an infant period of human. The cultivated tooth germs and renal calcified teeth were examined by histology and immunohistochemical analysis. Our results revealed that treatment of 4PBA altered expression patterns of enamel knot related signaling molecules, and consequently affected cellular secretion and patterned formation of dental hard tissues including dentin and enamel during tooth morphogenesis. The alteration of ER stress by 4PBA treatment during organogenesis would suggest that proper ER stress is important for pattern formation during tooth development and morphogenesis, and 4PBA as a chemical chaperone would be one of the candidate molecules for dental and hard tissue regeneration.
在牙齿发育过程中，随着新合成的蛋白质逐渐形成特定组织，正确的蛋白质折叠和运输是重要过程。内质网（ER）应激在牙齿发育过程中不可避免地发生，因为未折叠和错误折叠的蛋白质在内质网中积累。4-苯基丁酸（4PBA）是一种经美国食品药品监督管理局（FDA）批准的药物，被称为化学伴侣，可减轻内质网应激。最近，多项研究表明，4PBA在一些因蛋白质错误折叠导致的遗传性疾病、代谢相关疾病以及内质网应激引起的细胞凋亡中发挥治疗作用。然而，4PBA在牙齿发生过程中的作用尚未阐明。本研究揭示了4PBA在小鼠磨牙发育过程中的作用。我们采用了体外器官培养和肾移植方法，这些方法可模拟人类婴儿期恒牙的发育过程。通过组织学和免疫组织化学分析对培养的牙胚和肾钙化牙进行检查。我们的结果显示，4PBA处理改变了釉结相关信号分子的表达模式，进而在牙齿形态发生过程中影响了包括牙本质和牙釉质在内的牙齿硬组织的细胞分泌和模式形成。器官发生过程中4PBA处理对内质网应激的改变表明，适当的内质网应激对牙齿发育和形态发生过程中的模式形成很重要，而4PBA作为一种化学伴侣将是牙齿和硬组织再生的候选分子之一。
