Department of Pediatric Dentistry, Division of Oral Health, Growth and Development, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Department of Molecular Cell Biology and Oral Anatomy, Division of Oral Biological Sciences, Kyushu University Graduate School of Dental Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Stem Cell Res Ther. 2018 Nov 8;9(1):303. doi: 10.1186/s13287-018-1042-7.
Hyperbilirubinemia that occurs in pediatric liver diseases such as biliary atresia can result in the development of not only jaundice in the brain, eyes, and skin, but also tooth abnormalities including green pigmentation and dentin hypoplasia in the developing teeth. However, hyperbilirubinemia-induced tooth impairments remain after liver transplantation. No effective dental management to prevent hyperbilirubinemia-induced tooth impairments has been established.
In this study, we focused on pamidronate, which is used to treat pediatric osteopenia, and investigated its effects on hyperbilirubinemia-induced tooth impairments. We cultured stem cells from human exfoliated deciduous teeth (SHED) under high and low concentrations of unconjugated bilirubin in the presence or absence of pamidronate. We then analyzed the effects of pamidronate on the cell death, associated signal pathways, and dentinogenic function in SHED.
We demonstrated that a high concentration of unconjugated bilirubin induced cell death in SHED via the mitochondrial pathway, and this was associated with the suppression of AKT and extracellular signal-related kinase 1 and 2 (ERK1/2) signal pathways and activation of the nuclear factor kappa B (NF-κB) signal pathway. The high concentration of unconjugated bilirubin impaired the in vitro and in vivo dentinogenic capacity of SHED, but not the low concentration. We then demonstrated that pamidronate decreased the bilirubin-induced cell death in SHED via the altered AKT, ERK1/2, and NF-κB signal pathways and recovered the bilirubin-impaired dentinogenic function of SHED.
Our findings suggest that pamidronate may prevent tooth abnormalities in pediatric patients with hyperbilirubinemia.
胆道闭锁等儿科肝病引起的高胆红素血症不仅会导致脑、眼和皮肤发黄，还会导致牙齿发育异常，包括牙齿出现绿色色素沉着和牙本质发育不全。然而，肝移植后仍会发生高胆红素血症引起的牙齿损伤。目前尚未建立有效的牙科管理措施来预防高胆红素血症引起的牙齿损伤。
在这项研究中，我们专注于用于治疗儿童骨质疏松症的帕米膦酸，并研究了其对高胆红素血症引起的牙齿损伤的影响。我们在高、低浓度未结合胆红素存在或不存在帕米膦酸的情况下培养人乳牙脱落干细胞（SHED）。然后，我们分析了帕米膦酸对 SHED 细胞死亡、相关信号通路和牙本质生成功能的影响。
我们证明，高浓度未结合胆红素通过线粒体途径诱导 SHED 细胞死亡，这与 AKT 和细胞外信号调节激酶 1 和 2（ERK1/2）信号通路的抑制以及核因子 kappa B（NF-κB）信号通路的激活有关。高浓度未结合胆红素损害了 SHED 的体外和体内牙本质生成能力，但低浓度未结合胆红素没有。然后，我们证明帕米膦酸通过改变 AKT、ERK1/2 和 NF-κB 信号通路降低了 SHED 中胆红素诱导的细胞死亡，并恢复了胆红素损害的 SHED 牙本质生成功能。
我们的研究结果表明，帕米膦酸可能预防高胆红素血症儿科患者的牙齿异常。
