Facilitation of Reparative Dentin Using a Drug Repositioning Approach With 4-Phenylbutric Acid

Eui-Seon Lee; Yam Prasad Aryal; Tae-Young Kim; Ji-Youn Kim; Hitoshi Yamamoto; Chang-Hyeon An; Seo-Young An; Youngkyun Lee; Wern-Joo Sohn; Jae-Kwang Jung; Jung-Hong Ha; Jae-Young Kim

doi:10.3389/fphys.2022.885593

Facilitation of Reparative Dentin Using a Drug Repositioning Approach With 4-Phenylbutric Acid

Front Physiol. 2022 May 4:13:885593. doi: 10.3389/fphys.2022.885593. eCollection 2022.

Authors

Affiliations

¹ Department of Biochemistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, Korea.
² Department of Dental Hygiene, Gachon University, Incheon, South Korea.
³ Department of Histology and Developmental Biology, Tokyo Dental College, Tokyo, Japan.
⁴ Department of Oral and Maxillofacial Radiology, School of Dentistry, IHBR, Kyungpook National University, Daegu, Korea.
⁵ Pre-Major of Cosmetics and Pharmaceutics, Daegu Haany University, Gyeongsan, South Korea.
⁶ Department of Oral Medicine, School of Dentistry, IHBR, Kyungpook National University, Daegu, Korea.
⁷ Department of Conservative Dentistry, School of Dentistry, IHBR, Kyungpook National University, Daegu, South Korea.

Abstract

For hard tissue formation, cellular mechanisms, involved in protein folding, processing, and secretion play important roles in the endoplasmic reticulum (ER). In pathological and regeneration conditions, ER stress hinders proper formation and secretion of proteins, and tissue regeneration by unfolded protein synthesis. 4-Phenylbutyric acid (4PBA) is a chemical chaperone that alleviates ER stress through modulation in proteins folding and protein trafficking. However, previous studies about 4PBA only focused on the metabolic diseases rather than on hard tissue formation and regeneration. Herein, we evaluated the function of 4PBA in dentin regeneration using an exposed pulp animal model system via a local delivery method as a drug repositioning strategy. Our results showed altered morphological changes and cellular physiology with histology and immunohistochemistry. The 4PBA treatment modulated the inflammation reaction and resolved ER stress in the early stage of pulp exposure. In addition, 4PBA treatment activated blood vessel formation and TGF-β1 expression in the dentin-pulp complex. Micro-computed tomography and histological examinations confirmed the facilitated formation of the dentin bridge in the 4PBA-treated specimens. These results suggest that proper modulation of ER stress would be an important factor for secretion and patterned formation in dentin regeneration.

Keywords: cavity preparation; chemical chaperone; dentin-pulp complex; drug repositioning; reparative dentin formation.