Pamidronate decreases bilirubin-impaired cell death and improves dentinogenic dysfunction of stem cells from human deciduous teeth.
Pamidronate decreases bilirubin-impaired cell death and improves dentinogenic dysfunction of stem cells from human deciduous teeth.
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DOI：
10.1186/s13287-018-1042-7
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发表时间：
2018-11-08
影响因子：
7.5
通讯作者：
Yamaza T
中科院分区：
文献类型：
--
作者：
Yamaza H;Sonoda S;Nonaka K;Kukita T;Yamaza T
胆道闭锁等小儿肝脏疾病中发生的高胆红素血症不仅会导致大脑、眼睛和皮肤黄疸，还会导致牙齿异常，包括发育中牙齿的绿色色素沉着和牙本质发育不全。然而，肝移植后高胆红素血症引起的牙齿损伤仍然存在。尚未建立有效的牙科治疗方法来预防高胆红素血症引起的牙齿损伤。在这项研究中，我们重点关注用于治疗儿童骨质减少的帕米膦酸，并研究其对高胆红素血症引起的牙齿损伤的影响。我们在存在或不存在帕米磷酸的情况下，在高浓度和低浓度的非结合胆红素下培养来自人类脱落乳牙（SHED）的干细胞。然后我们分析了帕米膦酸钠对 SHED 中细胞死亡、相关信号通路和牙本质功能的影响。我们证明，高浓度的未结合胆红素通过线粒体途径诱导 SHED 细胞死亡，这与 AKT 和细胞外信号相关激酶 1 和 2 (ERK1/2) 信号途径的抑制以及核因子 kappa B (NF-κB) 信号途径的激活有关。高浓度非结合胆红素会损害SHED的体外和体内牙本质形成能力，但低浓度则不会。然后我们证明帕米膦酸通过改变 AKT、ERK1/2 和 NF-κB 信号通路减少 SHED 中胆红素诱导的细胞死亡，并恢复 SHED 胆红素受损的牙本质功能。我们的研究结果表明，帕米膦酸可以预防高胆红素血症儿科患者的牙齿异常。本文的在线版本 (10.1186/s13287-018-1042-7) 包含补充材料，可供授权用户使用。
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. The online version of this article (10.1186/s13287-018-1042-7) contains supplementary material, which is available to authorized users.
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