Dexamethasone induces ferroptosis in MC3T3-E1 cells by promoting DNMT3a-mediated Sirt1 DNA hypermethylation in the context of steroid-induced osteonecrosis of the femoral head

Abstract

Ferroptosis, a novel form of regulated necrosis, has drawn the attention of the scientific community. Nevertheless, few studies have focused on the impact of ferroptosis on MC3T3-E1 cells in the context of steroid-induced osteonecrosis of the femoral head (SONFH). In this study, we explore the relationship between the degree of ferroptosis induced by dexamethasone (Dex) and the expression of silent information regulatory protein 1 (Sirt1). The results indicate that the ferroptosis level induced by Dex is mediated by the downregulation of Sirt1. Overexpression of Sirt1 increases the levels of the ferroptosis-related proteins SLC7A11 and GPX4 in MC3T3-E1 cells following Dex exposure. Moreover, the effect of Dex on Sirt1 expression is regulated by hypermethylation of the Sirt1 promoter, which is catalyzed by DNA methyltransferase 3a (DNMT3a). In summary, this study reveals that Dex can trigger ferroptosis by promoting DNMT3a-mediated DNA methylation and downregulating Sirt1 expression. Our findings provide an additional new mechanism for Dex-induced ferroptosis in MC3T3-E1 cells.

1. Introduction

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive bone disorder that occurs due to ischemic necrosis of the subchondral bone and osteocytes resulting from prolonged or excessive glucocorticoid usage [1]. This condition, which is common among young and middle-aged people, poses significant therapeutic challenges because of its complex pathophysiology involving vascular endothelial dysfunction, cell apoptosis, intraosseous hypertension, lipid metabolism dysregulation, and abnormal bone remodelling [2,3]. Without timely intervention, SONFH often progresses to femoral head collapse and secondary osteoarthritis, resulting in total hip arthroplasty in advanced cases [1]. Current management strategies focus on early diagnosis by imaging modalities such as MRI, along with interventions ranging from pharmacological approaches (anticoagulants, vasodilators) to surgical options (core decompression, bone grafting) [4]. However, the efficacy of treatment remains limited, highlighting the necessity for further research on targeted therapies that address the multifactorial pathogenesis of SONFH.

Osteoblasts are crucial cells in bone formation. Recent studies have revealed significant changes in osteoblast function in SONFH, featuring dysregulation of bone formation, mineralization, and osteogenic marker expressions [5]. Elucidating the molecular mechanisms underlying osteoblast dysfunction provides insights into potential therapeutic targets for SONFH.

Ferroptosis is a newly identified form of programmed cell death that is iron-dependent and distinct from apoptosis, necrosis, and autophagy [6]. Its occurrence is associated with abnormal cellular iron metabolism and lipid peroxidation. Key features include alterations in mitochondria, elevated intracellular iron levels, accumulation of ROS, and build-up of lipid metabolites [7]. GPX4 detoxifies hydrogen peroxide in lipids, safeguarding membranes against oxidative damage [8]. Recently, ferroptosis has emerged as a critical factor in various bone-related disorders. Evidence suggests that glucocorticoids might disrupt iron metabolism and redox homeostasis, potentially inducing ferroptosis in osteoblasts, osteocytes, and BMSCs, thereby contributing to SONFH development [9,10]. This study explored the potential link between ferroptosis and SONFH, identifying novel therapeutic targets for its prevention and treatment.