2. Academic Validation
  3. ERS Mediated by GRP-78/PERK/CHOP Signaling Is Involved in Fluoride-Induced Ameloblast Apoptosis

ERS Mediated by GRP-78/PERK/CHOP Signaling Is Involved in Fluoride-Induced Ameloblast Apoptosis

  • Biol Trace Elem Res. 2023 Jul 6. doi: 10.1007/s12011-023-03746-5.
Li Jinyi 1 2,  Yang Keyu 3,  Dai Shanshan 1 2,  He Shuyang 4,  Liu Ruirui 1 5,  Guo Qingyu 6 7,  Liu Fei 8 9
Affiliations

Affiliations

  • 1 Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.
  • 2 Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China.
  • 3 National Regional Children's Medical Center (Northwest), Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, 710003, People's Republic of China.
  • 4 Faculty of dentistry, The university of Hong Kong, Hong Kong, SAR, People's Republic of China.
  • 5 Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China.
  • 6 Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China. guoqinyu@mail.xjtu.edu.cn.
  • 7 Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China. guoqinyu@mail.xjtu.edu.cn.
  • 8 Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi'an, 710004, People's Republic of China. liufei6630@mail.xjtu.edu.cn.
  • 9 Department of Pediatric Dentistry, College of Stomatology, Xi'an Jiaotong University, Xi Wu Road No.98, Xi'an 710004, 710041, People's Republic of China. liufei6630@mail.xjtu.edu.cn.
PMID: 37410266 DOI: 10.1007/s12011-023-03746-5
Abstract

Fluoride can be widely ingested from the environment, and its excessive intake could result in adverse effects. Dental fluorosis is an early sign of fluoride toxicity which can cause esthetic and functional problems. Though Apoptosis in ameloblasts is one of the potential mechanisms, the specific signal cascade is in-conclusive. High-throughput sequencing and molecular biological techniques were used in this study to explore the underlying pathogenesis of dental fluorosis, for its prevention and treatment. A fluorosis cell model was established. Viability and Apoptosis rate of mouse ameloblast-derived cell line (LS8 cells) was measured using cell counting kit-8 (CCK-8) assay and flow cytometry analysis. Cells were harvested with or without 2-mM sodium fluoride (NaF) stimulation for high-throughput sequencing. Based on the sequencing data, subcellular structures, endoplasmic reticulum stress (ERS), and Apoptosis related biomarkers were verified using transmission electron microscopy, quantitative real-time polymerase chain reaction, and Western blotting techniques. Expression of ERS markers, Apoptosis related proteins, and enamel formation enzymes were detected using Western blotting after addition of 4-phenylbutyrate (4-PBA). NaF-inhibited LS8 cells displayed time- and dose- dependent viability. Additionally, Apoptosis and morphological changes were observed. RNA-sequencing data showed that protein processing in endoplasmic reticulum was obviously affected. ERS and Apoptosis were induced by excessive NaF. Downregulation of kallikrein-related peptidase 4 (KLK4) was also observed. Inhibition of ERS by 4-PBA rescued the apoptotic and functional protein changes in cells. Excessive fluoride induces Apoptosis by activating ERS, which is mediated by GRP-78/PERK/CHOP signaling. Key proteinase is present in maturation-stage enamel; KLK4 was also affected by fluoride, but rescued by 4-PBA. This study presents a possibility for therapeutic strategies for dental fluorosis, while further exploration is required.

Keywords

Apoptosis; Dental fluorosis; Endoplasmic reticulum stress; Li and Yang contributed equally to this work.; Mouse ameloblast-derived cell line.

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