Inhibiting DNA methyltransferase DNMT3B confers protection against ferroptosis in nucleus pulposus and ameliorates intervertebral disc degeneration via upregulating SLC40A1.

Autor: Chen J; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China., Yang X; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China., Li Q; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China., Ma J; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China., Li H; Department of Emergency, Chongqing University Three Gorges Hospital, Chongqing, 404000, China., Wang L; Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China., Chen Z; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China., Quan Z; Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, China. Electronic address: 201818@hospital.cqmu.edu.cn.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2024 Aug 01; Vol. 220, pp. 139-153. Date of Electronic Publication: 2024 May 03.
DOI: 10.1016/j.freeradbiomed.2024.05.007
Abstrakt: Epigenetic changes are important considerations for degenerative diseases. DNA methylation regulates crucial genes by epigenetic mechanism, impacting cell function and fate. DNA presents hypermethylation in degenerated nucleus pulposus (NP) tissue, but its role in intervertebral disc degeneration (IVDD) remains elusive. This study aimed to demonstrate that methyltransferase mediated hypermethylation was responsible for IVDD by integrative bioinformatics and experimental verification. Methyltransferase DNMT3B was highly expressed in severely degenerated NP tissue (involving human and rats) and in-vitro degenerated human NP cells (NPCs). Bioinformatics elucidated that hypermethylated genes were enriched in oxidative stress and ferroptosis, and the ferroptosis suppressor gene SLC40A1 was identified with lower expression and higher methylation in severely degenerated human NP tissue. Cell culture using human NPCs showed that DNMT3B induced ferroptosis and oxidative stress in NPCs by downregulating SLC40A1, promoting a degenerative cell phenotype. An in-vivo rat IVDD model showed that DNA methyltransferase inhibitor 5-AZA alleviated puncture-induced IVDD. Taken together, DNA methyltransferase DNMT3B aggravates ferroptosis and oxidative stress in NPCs via regulating SLC40A1. Epigenetic mechanism within DNA methylation is a promising therapeutic biomarker for IVDD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this study.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: