Functional Study of the circRNA_0006393/miR-375/IGFBP4 Axis in Fracture Healing Associated with Male Idiopathic Osteoporosis

  • J Invest Surg. 2025 Dec;38(1):2535522. doi: 10.1080/08941939.2025.2535522.
Xiaoyi Guo  1 ,  Jie Xu  2  3 ,  Lin Chen  4 ,  He Huang  5 ,  Zewei Gao  4 ,  Xijia Jiang  2  3
Affiliations
  • 1. Sports Medicine Department, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, China.
  • 2. Department of Orthopedics, Changzhou Second People's Hospital, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, China.
  • 3. Changzhou Medical Center, Nanjing Medical University, Changzhou, China.
  • 4. Department of Orthopedics I, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 5. Emergency Department, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
PMID: 40728000 DOI: 10.1080/08941939.2025.2535522
Abstract

Background: CircRNA_0006393 was reported to promote osteogenesis in glucocorticoid-induced osteoporosis, but its role in male idiopathic osteoporosis (MIO) has not been revealed.

Aim: To explore circRNA_0006393's role in MIO.

Methods: Dual-luciferase reporter assay was performed to notarize the direct connection among circRNA_0006393, miR-375 and IGFBP4. Their value as biomarkers of MIO was confirmed by the ROC curve. The osteogenic induction was measured by detecting the ALP activity/expression and OCN/RUNX2 expression. The osteoclastic induction was evaluated by detecting TRAP activity and bone resorption capacity. The concentration of Fe2+, GSH, and ROS was detected to evaluate Ferroptosis.

Results: MiR-375 was overexpressed in MIO patients, while circRNA_000639 and IGFBP4 presented low expression. CircRNA_0006393 promoted IGFBP4 expression by sponging miR-375. The AUC of circulating circRNA_0006393, miR-375, IGFBP4, or their combination in distinguishing unhealing and healing individuals with MIO-related fracture was 0.840, 0.851, 0.743, 0.960, respectively. CircRNA_0006393 reduced the Ferroptosis process by regulating miR-375/IGFBP4. Iron overload inhibited the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSC) and promoted the osteoclastic differentiation of bone marrow-derived macrophage cells (BMMC).

Conclusion: CircRNA_000639 inhibited Ferroptosis by regulating the miR-375/IGFBP4 axis, thereby promoting osteogenesis and hindering osteoclastic differentiation, and they are the biomarkers for MIO-related fracture healing.

Keywords
IGFBP4; circRNA_0006393; ferroptosis; male idiopathic osteoporosis; miR-375.
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