2. Academic Validation
  3. Inhibition of insulin degrading enzyme suppresses osteoclast hyperactivity via enhancing Nrf2-dependent antioxidant response in glucocorticoid-induced osteonecrosis of the femoral head

Inhibition of insulin degrading enzyme suppresses osteoclast hyperactivity via enhancing Nrf2-dependent antioxidant response in glucocorticoid-induced osteonecrosis of the femoral head

  • Mol Med. 2024 Jul 31;30(1):111. doi: 10.1186/s10020-024-00880-1.
Tao Yuan # 1,  Haojue Wang # 1,  Yi Wang 2 3,  Shankun Dong 1,  Jianxun Ge 1,  Ziqing Li 4 5,  Shui Sun 6 7 8
Affiliations

Affiliations

  • 1 Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 2 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 3 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China.
  • 4 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. liziqing@sdfmu.edu.cn.
  • 5 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. liziqing@sdfmu.edu.cn.
  • 6 Department of Joint Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. sunshui@sdfmu.edu.cn.
  • 7 Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. sunshui@sdfmu.edu.cn.
  • 8 Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, China. sunshui@sdfmu.edu.cn.
  • # Contributed equally.
PMID: 39085816 DOI: 10.1186/s10020-024-00880-1
Abstract

Background: Osteoclast hyperactivation due to the pathological overproduction of Reactive Oxygen Species (ROS) stimulated by glucocorticoids (GCs) is one of the key drivers behind glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). The Insulin degrading Enzyme (IDE), a conserved Zn2+ metallo-endopeptidase, facilitates the DNA binding of Glucocorticoid Receptor and plays a substantial role in steroid hormone-related signaling pathways. However, the potential role of IDE in the pathogenesis of GIONFH is yet undefined.

Methods: In this study, we employed network pharmacology and bioinformatics analysis to explore the impact of IDE inhibition on GIONFH with 6bK as an inhibitory agent. Further evidence was collected through in vitro osteoclastogenesis experiments and in vivo evaluations involving methylprednisolone (MPS)-induced GIONFH mouse model.

Results: Enrichment analysis indicated a potential role of 6bK in redox regulation amid GIONFH development. In vitro findings revealed that 6bK could attenuate GCs-stimulated overactivation of osteoclast differentiation by interfering with the transcription and expression of key osteoclastic genes (Traf6, Nfatc1, and Ctsk). The use of an H2DCFDA probe and subsequent WB assays introduced the inhibitory effects of 6bK on osteoclastogenesis, linked with the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-mediated antioxidant system. Furthermore, Micro-CT scans validated that 6bK could alleviate GIONFH in MPS-induced mouse models.

Conclusions: Our findings suggest that 6bK suppresses osteoclast hyperactivity in GCs-rich environment. This is achieved by reducing the accumulation of intracellular ROS via promoting the Nrf2-mediated antioxidant system, thus implying that IDE could be a promising therapeutic target for GIONFH.

Keywords

Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH); Glucocorticoids (GCs); Insulin degrading enzyme (IDE); Osteoclast; Reactive oxygen species (ROS).

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