2. Academic Validation
  3. Asperosaponin VI inhibition of DNMT alleviates GPX4 suppression-mediated osteoblast ferroptosis and diabetic osteoporosis

Asperosaponin VI inhibition of DNMT alleviates GPX4 suppression-mediated osteoblast ferroptosis and diabetic osteoporosis

  • J Adv Res. 2024 Dec 6:S2090-1232(24)00554-X. doi: 10.1016/j.jare.2024.11.036.
Fanhao Wei 1,  Binjia Ruan 2,  Jian Dong 3,  Bin Yang 4,  Guofu Zhang 4,  Wai Kwok Kelvin Yeung 5,  Hongwei Wang 6,  Wangsen Cao 7,  Yongxiang Wang 8
Affiliations

Affiliations

  • 1 Department of Graduate School, Dalian Medical University, No.9 of West Section of Lushun South Road, Dalian 116044, China; The Yangzhou School of Clinical Medicine of Dalian Medical University, 98 West Nantong Road, Yangzhou 225001, China.
  • 2 Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, 98 West Nantong Road, Yangzhou 225001, China.
  • 3 Department of Thoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210093, China.
  • 4 Department of Orthopaedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 98 West Nantong Road, Yangzhou 225001, China.
  • 5 Department of Orthopaedics and Traumatology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 6 Nanjing University Medical School, Jiangsu Key Lab of Molecular Medicine, 22 Hankou Road, Nanjing 210093, China. Electronic address: hwang@nju.edu.cn.
  • 7 Department of Orthopaedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 98 West Nantong Road, Yangzhou 225001, China; Nanjing University Medical School, Jiangsu Key Lab of Molecular Medicine, 22 Hankou Road, Nanjing 210093, China; Yancheng First People's Hospital, Affiliated Hospital of Nanjing University Medical School, South People's Road, Yancheng 224006, China.. Electronic address: wangsencao@nju.edu.cn.
  • 8 Department of Orthopaedics, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 98 West Nantong Road, Yangzhou 225001, China; Department of Orthopaedics, Northern Jiangsu People's Hospital, 98 West Nantong Road, Yangzhou 225001, China; The Yangzhou School of Clinical Medicine of Dalian Medical University, 98 West Nantong Road, Yangzhou 225001, China; Northern Jiangsu People's Hospital, Clinical Teaching Hospital of Medical School, Nanjing University, 98 West Nantong Road, Yangzhou 225001, China. Electronic address: wyx918spine@yzu.edu.cn.
PMID: 39647633 DOI: 10.1016/j.jare.2024.11.036
Abstract

Introduction: Diabetic osteoporosis (DOP) is an insidious complication of diabetes with limited therapeutic options. DOP is pathologically associated with various types of regulated cell death, but the precise role of Ferroptosis in the process remains poorly understood. Asperosaponin VI (AVI), known for its clinical efficacy in treating bone fractures and osteoporosis, may exert its osteoprotective effects through mechanisms involving Ferroptosis, however this has not been established.

Objectives: This study aimed to investigate the role of AVI in modulating Ferroptosis in a mouse model of DOP and to explore the underlying mechanisms.

Methods: We assessed OP alterations in femurs of DOP-conditioned mice and primary bone cells. We generated a strain of osteoblast-specific Gpx4-deficient mice. A combination of micro-CT, immunohistochemistry, immunofluorescence, methylation-specific PCR (MSP), bisulfite Sequencing PCR (BSP), western blotting (WB), and AVI pull-down assays were employed to elucidate the mechanism and therapeutic target of AVI in DOP.

Results: Our findings revealed that femurs from DOP-conditioned mice exhibited significant Ferroptosis and suppression of the core anti-ferroptosis factor GPX4, mainly due to hypermethylation of the Gpx4 promoter mediated by DNA methyltransferases DNMT1and DNMT3a. Notably, treatment with AVI effectively reversed the hypermethylation, restored GPX4 expression, and reduced ferroptotic pathologies associated with DOP by inhibiting DNMT1/3a. In primarily-cultured osteoblasts and osteoclasts, AVI alleviated GPX4 suppression and reduced Ferroptosis in DOP-conditioned osteoblasts through a mechanism dependent on DNMT inhibition and GPX4 restoration. Importantly, the anti-ferroptotic and osteoprotective effects of AVI were abolished in osteoblastic Gpx4 haplo-deficient mice (Gpx4Ob-/+) or when GPX4 was pharmacologically inactivated with RSL3.

Conclusions: Our study identifies a pivotal epigenetic ferroptotic pathway that contributes significantly to DOP and uncovers a crucial pharmacological property of AVI that is potentially effective in treating patients with DOP and related osteoporotic disorders.

Keywords

Asperosaponin VI; DNA methylation; Diabetic Osteoporosis; Ferroptosis; GPX4.

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