Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin

Peilin Meng; Huan Liu; Li Liu; Yan Wen; Feng'e Zhang; Yanan Zhang; Yumeng Jia; Yingang Zhang; Feng Zhang; Xiong Guo

doi:10.1016/j.fct.2024.114724

Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin

Food Chem Toxicol. 2024 May 10:189:114724. doi: 10.1016/j.fct.2024.114724. Online ahead of print.

Authors

Peilin Meng¹, Huan Liu¹, Li Liu¹, Yan Wen¹, Feng'e Zhang¹, Yanan Zhang², Yumeng Jia¹, Yingang Zhang³, Feng Zhang⁴, Xiong Guo⁵

Affiliations

¹ School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission and Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, Xi'an, 710061, PR China.
² School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission and Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, Xi'an, 710061, PR China; School of Nursing, Lanzhou University, Lanzhou, 730000, PR China.
³ Department of Orthopaedics of the First Affiliated Hospital, Medical School, Xi'an Jiaotong University, Xi'an, 710061, PR China.
⁴ School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission and Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, Xi'an, 710061, PR China. Electronic address: fzhxjtu@xjtu.edu.cn.
⁵ School of Public Health, Health Science Center of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory of Trace Elements and Endemic Diseases of National Health Commission and Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, Xi'an, 710061, PR China; Clinical Research Center for Endemic Disease of Shaanxi Province, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, PR China. Electronic address: guox@xjtu.edu.cn.

PMID: 38734200
DOI: 10.1016/j.fct.2024.114724

Abstract

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-Chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

Keywords: Cell homeostasis; Extracellular matrix degradation; HT-2 toxin; Human induced pluripotent stem cells chondrocytes; Notch signaling pathway.