Copyright
©The Author(s) 2026. Published by Baishideng Publishing Group Inc. All rights reserved.
Endothelial cell-derived exosomes inhibit high glucose-induced osteoblast ferroptosis by activating microRNA-335-3p/prostaglandin endoperoxide synthase 2
Chen Shao, Li-Jian Zhang, Yi-Lin Song, Yan-Qiu Wang, Xiu-Jing Zha, Juan Li, Cheng-Song Ye, Ling-Ling Chen, Ming-Wei Chen, Guo-Xi Jin
Chen Shao, Ming-Wei Chen, Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui Province, China
Chen Shao, Yan-Qiu Wang, Xiu-Jing Zha, Juan Li, Cheng-Song Ye, Department of Endocrinology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Li-Jian Zhang, Guo-Xi Jin, Department of Endocrinology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, Anhui Province, China
Yi-Lin Song, Department of Nephrology, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Ling-Ling Chen, Department of Nursing, The Second Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Co-corresponding authors: Ming-Wei Chen and Guo-Xi Jin.
Author contributions: Shao C led the experimental design and implementation, responsible for data analysis and main writing and revision of the paper; Zhang LJ participated in the formulation and execution of the experimental plan, assisted in data organization and analysis; Song YL was responsible for the preparation of experimental materials and part of the data processing work; Wang YQ participated in experimental operations, and was responsible for recording and preliminary analysis of experimental data; Zha XJ assisted in experimental design and implementation, provided necessary technical support; Li J participated in data collection and organization, proofread the paper; Li J and Chen MW participated in the revision of the paper; Ye CS and Chen LL were responsible for the maintenance of experimental equipment and data collection; Chen MW provided suggestions for experimental design, participated in the discussion of the paper; Jin GX was responsible for overall project guidance and supervision, conducted the final review and approval of the paper; Chen MW and Jin GX made equal contributions as co-corresponding authors. All authors approved the final version to publish.
Supported by Natural Science Projects of Bengbu Medical College, No. 2022byzd088; Anhui Province Higher Education Scientific Research Project, No. 2024AH051285; Anhui Provincial Department of Education Humanities and Social Science Key Project, No. 2023AH051900; and the Key Research and Development Program Projects of Anhui Province, No. 202204295107020049.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of Bengbu Medical University, No. [2023]269.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data generated during and/or analyzed during the present study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Guo-Xi Jin, PhD, Chief Physician, Professor, Department of Endoc
rinology, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Road, Bengbu 233004, Anhui Province, China.
jinguoxi@bbmu.edu.cn
Received: June 25, 2025
Revised: July 21, 2025
Accepted: December 2, 2025
Published online: January 15, 2026
Processing time: 204 Days and 1.5 Hours
BACKGROUND
Diabetic osteoporosis (DOP), a serious complication of type 2 diabetes mellitus (T2DM), involves ferroptosis-mediated disruption of bone metabolism. While endothelial cell-derived exosomes (EC-Exos) demonstrate inherent bone-targeting properties, their role in counteracting high glucose (HG)-induced osteoblast ferroptosis remains unexplored.
AIM
To investigate whether EC-Exos protect against HG-induced osteoblast ferroptosis through microRNA (miR)-335-3p-mediated regulation of prostaglandin endoperoxide synthase 2 (PTGS2) and evaluate clinical relevance in DOP.
METHODS
Mouse vascular endothelial cells (bEND.3) and osteoblasts (MC3T3E1) were used. Exosomes were isolated and subsequently characterized by transmission electron microscopy, nanoparticle tracking analysis, and western blotting for CD63 and CD81. miR expression profiles were compared between HG-treated osteoblasts and exosome-cocultured groups using high-throughput sequencing and quantitative reverse transcription polymerase chain reaction. Targeting of PTGS2 mRNA by miR-335-3p was validated by dual-luciferase reporter assay. Ferroptosis markers, reactive oxygen species, malondialdehyde, glutathione (GSH), PTGS2, GSH peroxidase 4, solute carrier family 7 member 11, and solute carrier family 3 member 2, were quantified following miR-335-3p inhibition. Serum samples from 30 T2DM patients and 32 DOP patients were analyzed. miR-335-3p levels were measured by quantitative reverse transcription polymerase chain reaction, and PTGS2 concentrations were determined via enzyme-linked immunosorbent assay. Diagnostic performance was assessed using receiver operating characteristic curves and logistic regression.
RESULTS
EC-Exos significantly reduced reactive oxygen species levels and malondialdehyde, while increasing GSH in HG-treated osteoblasts. miR-335-3p expression increased 3.7-fold in exosome-treated cells vs HG controls. miR-335-3p directly bound the PTGS2 3’ untranslated region. Inhibition of miR-335-3p abolished exosomal protection against ferroptosis, as demonstrated by increased PTGS2 expression and reduced levels of GSH peroxidase 4, solute carrier family 7 member 11, and solute carrier family 3 member 2. DOP patients exhibited lower serum miR-335-3p and higher PTGS2 compared with T2DM controls, showing a strong inverse correlation. miR-335-3p demonstrated diagnostic potential for DOP.
CONCLUSION
EC-Exos affect ferroptosis in osteoblasts induced by HG by activating miR-335-3p/PTGS2. Serum miR-335-3p may be a novel diagnostic biomarker.
Core Tip: Endothelial cell-derived exosomes demonstrate inherent bone-targeting properties, their role in counteracting high glucose-induced osteoblast ferroptosis remains unexplored. This study reveals that endothelial cell-derived exosomes protect osteoblasts from high glucose-induced ferroptosis by regulating microRNA-335-3p/prostaglandin endoperoxide synthase 2. The diagnostic potential of serum microRNA-335-3p for diabetic osteoporosis was demonstrated, warranting further validation with an expanded sample size.
