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Stem Cell Res Ther. 2018 Nov 8;9(1):303. doi: 10.1186/s13287-018-1042-7.

Pamidronate decreases bilirubin-impaired cell death and improves dentinogenic dysfunction of stem cells from human deciduous teeth.

Author information

1
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. hyamaza@dent.kyushu-u.ac.jp.
2
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.
3
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.
4
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. yamazata@dent.kyushu-u.ac.jp.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

Our findings suggest that pamidronate may prevent tooth abnormalities in pediatric patients with hyperbilirubinemia.

KEYWORDS:

Bilirubin; Cell death; Pamidronate; Stem cells from human exfoliated deciduous teeth (SHED)

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