Objective: Glucocorticoid-induced osteonecrosis of the femoral head (GC-ONFH) represents a devastating complication of steroid therapy, primarily driven by osteoblast apoptosis and impaired osteogenesis. Although selenium (Se) is renowned for its potent bone-protective properties, its therapeutic potential, and specific mechanisms in GC-ONFH remain largely unexplored and thus require further investigation.
Methods: To assess the therapeutic effectiveness of oral selenium supplementation in GC-ONFH, a rat model of GC-ONFH was utilized. The rats were randomly allocated into three groups (n = 6 per group): (1) Control group, (2) Methylprednisolone sodium succinate (MPS) group, and (3) Se group. The intervention was carried out for 4 weeks. In vitro experiments utilized primary rat osteoblasts and MC3T3-E1 cells to elucidate the mechanisms through which selenium mitigates dexamethasone (DEX)-induced alterations in cell proliferation, apoptosis, and osteogenic differentiation. The assessments were conducted using micro-CT and histomorphometry, CCK-8 assays and flow cytometry, as well as RT–qPCR, Western blotting, and immunofluorescence.
Results: Selenium supplementation effectively prevented trabecular collapse and significantly reduced the number of empty lacunae in rats with GC-ONFH. Specifically, an optimal dose of 10 μmol Se successfully reversed the damage induced by DEX, including the restoration of cell proliferation, suppression of apoptosis, and rescue of osteogenic activity. Mechanistically, Se counteracts the DEX-induced suppression of phosphorylated phosphatidylinositol 3-kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase 3β (GSK3β) (p-GSK3β), thereby activating the PI3K/AKT/GSK3β signaling pathway, which promotes cell proliferation, inhibits apoptosis, and enhances osteogenesis in osteoblasts.
Conclusion: Selenium can activate the PI3K/AKT/GSK3β pathway, reverse DEX-induced hypoproliferation and apoptosis, restore osteogenic capacity, prevent trabecular collapse, and attenuate GC-ONFH in rat models. Our findings demonstrate that selenium supplementation can be regarded as a clinically applicable strategy for impeding the progression of GC-ONFH in at-risk patients.
| [1] |
C. Changjun, L. Donghai, Z. Xin, C. Liyile, W. Qiuru, and K. Pengde, “Mid- To Long-Term Results of Modified Non-Vascularized Allogeneic Fibula Grafting Combined With Core Decompression and Bone Grafting for Early Femoral Head Necrosis,” Journal of Orthopaedic Surgery and Research 15, no. 1 (2020): 116.
|
| [2] |
C. Chen, L. Fu, Y. Luo, et al., “Engineered Exosome-Functionalized Extracellular Matrix-Mimicking Hydrogel for Promoting Bone Repair in Glucocorticoid-Induced Osteonecrosis of the Femoral Head,” ACS Applied Materials & Interfaces 15, no. 24 (2023): 28891–28906.
|
| [3] |
C. Chen, X. Zhao, Y. Luo, et al., “Imbalanced T-Cell Subsets May Facilitate the Occurrence of Osteonecrosis of the Femoral Head,” Journal of Inflammation Research 15 (2022): 4159–4169.
|
| [4] |
C. Changjun, Z. Xin, A. Mohammed, C. Liyile, L. Yue, and K. Pengde, “Survivorship and Clinical Outcomes of “cup-Cage” Reconstruction in Revision of Hip Arthroplasty for Chronic Pelvic Discontinuity: A Systematic Review,” Surgeon 19, no. 6 (2021): e475–e484.
|
| [5] |
H. Yang, S. Nie, C. Zhou, et al., “Palliative Effect of Rotating Magnetic Field on Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats by Regulating Osteoblast Differentiation,” Biochemical and Biophysical Research Communications 725 (2024): 150265.
|
| [6] |
L. Mangiavini, G. M. Peretti, B. Canciani, and N. Maffulli, “Epidermal Growth Factor Signalling Pathway in Endochondral Ossification: an Evidence-Based Narrative Review,” Annals of Medicine 54, no. 1 (2022): 37–50.
|
| [7] |
A. Giai Via, M. B. McCarthy, L. de Girolamo, E. Ragni, F. Oliva, and N. Maffulli, “Making Them Commit: Strategies to Influence Phenotypic Differentiation in Mesenchymal Stem Cells,” Sports Medicine and Arthroscopy Review 26, no. 2 (2018): 64–69.
|
| [8] |
J. W. Lewis, K. Frost, G. Neag, et al., “Therapeutic Avenues in Bone Repair: Harnessing an Anabolic Osteopeptide, PEPITEM, to Boost Bone Growth and Prevent Bone Loss,” Cell Reports Medicine 5, no. 5 (2024): 101574.
|
| [9] |
M. S. Hansen, K. Søe, L. L. Christensen, et al., “GIP Reduces Osteoclast Activity and Improves Osteoblast Survival in Primary Human Bone Cells,” European Journal of Endocrinology 188, no. 1 (2023): 144–157.
|
| [10] |
A. G. Kay, T. P. Dale, K. M. Akram, et al., “BMP2 Repression and Optimized Culture Conditions Promote Human Bone Marrow-Derived Mesenchymal Stem Cell Isolation,” Regenerative Medicine 10, no. 2 (2015): 109–125.
|
| [11] |
S. Barnaba, R. Papalia, L. Ruzzini, A. Sgambato, N. Maffulli, and V. Denaro, “Effect of Pulsed Electromagnetic Fields on Human Osteoblast Cultures,” Physiotherapy Research International: the Journal for Researchers and Clinicians in Physical Therapy 18, no. 2 (2013): 109–114.
|
| [12] |
Y. Gao, Y. You, P. Zhang, et al., “Cortistatin Prevents Glucocorticoid-Associated Osteonecrosis of the Femoral Head via the GHSR1a/Akt Pathway,” Communications Biology 7, no. 1 (2024): 132.
|
| [13] |
S. C. Tao, T. Yuan, B. Y. Rui, Z. Z. Zhu, S. C. Guo, and C. Q. Zhang, “Exosomes Derived From Human Platelet-Rich Plasma Prevent Apoptosis Induced by Glucocorticoid-Associated Endoplasmic Reticulum Stress in Rat Osteonecrosis of the Femoral Head via the Akt/Bad/Bcl-2 Signal Pathway,” Theranostics 7, no. 3 (2017): 733–750.
|
| [14] |
J. Zhu, T. Zhao, L. Zhu, et al., “Dexamethasone Promotes Osteoblast Apoptosis Through the Chk2/p53 Signaling Pathway,” Advances in Clinical and Experimental Medicine 31, no. 12 (2022): 1365–1374.
|
| [15] |
C. Chen, M. Alqwbani, J. Zhao, R. Yang, S. Wang, and X. Pan, “Effects of Teriparatide Versus Salmon Calcitonin Therapy for the Treatment of Osteoporosis in Asia: A Meta-Analysis of Randomized Controlled Trials,” Endocrine, Metabolic & Immune Disorders Drug Targets 21, no. 5 (2021): 932–942.
|
| [16] |
X. X. Zhang, X. Liang, S. R. Li, K. J. Guo, D. F. Li, and T. F. Li, “Bone Marrow Mesenchymal Stem Cells Overexpressing HIF-1α Prevented the Progression of Glucocorticoid-Induced Avascular Osteonecrosis of Femoral Heads in Mice,” Cell Transplantation 31 (2022): 9636897221082687.
|
| [17] |
Y. Sun, M. Liang, Y. Xing, et al., “Cyasterone Has a Protective Effect on Steroid-Induced Osteonecrosis of the Femoral Head,” PLoS One 18, no. 10 (2023): e0293530.
|
| [18] |
F. Sun, J. L. Zhou, S. X. Wei, Z. W. Jiang, and H. Peng, “Glucocorticoids Induce Osteonecrosis of the Femoral Head in Rats via PI3K/AKT/FOXO1 Signaling Pathway,” PeerJ 10 (2022): e13319.
|
| [19] |
E. Eskandari and C. J. Eaves, “Paradoxical Roles of Caspase-3 in Regulating Cell Survival, Proliferation, and Tumorigenesis,” Journal of Cell Biology 221, no. 6 (2022): e202201159.
|
| [20] |
M. P. Rayman, “Selenium and Human Health,” Lancet 379, no. 9822 (2012): 1256–1268.
|
| [21] |
B. Zou, Z. Xiong, Y. Yu, S. Shi, X. Li, and T. Chen, “Rapid Selenoprotein Activation by Selenium Nanoparticles to Suppresses Osteoclastogenesis and Pathological Bone Loss,” Advanced Materials (Deerfield Beach, Fla) 36, no. 27 (2024): e2401620.
|
| [22] |
A. V. Skalny, M. Aschner, E. V. Silina, et al., “The Role of Trace Elements and Minerals in Osteoporosis,” A Review of Epidemiological and Laboratory Findings. Biomolecules 13, no. 6 (2023): 1006.
|
| [23] |
S. Fatima, R. Alfrayh, M. Alrashed, S. Alsobaie, R. Ahmad, and A. Mahmood, “Selenium Nanoparticles by Moderating Oxidative Stress Promote Differentiation of Mesenchymal Stem Cells to Osteoblasts,” International Journal of Nanomedicine 16 (2021): 331–343.
|
| [24] |
Y. Huang, Z. Jia, Y. Xu, M. Qin, and S. Feng, “Selenium Protects Against LPS-Induced MC3T3-E1 Cells Apoptosis Through Modulation of microRNA-155 and PI3K/Akt Signaling Pathways,” Genetics and Molecular Biology 43, no. 3 (2020): e20190153.
|
| [25] |
X. Zhao, C. Chen, Y. Luo, et al., “Connexin43 Overexpression Promotes Bone Regeneration by Osteogenesis and Angiogenesis in Rat Glucocorticoid-Induced Osteonecrosis of the Femoral Head,” Developmental Biology 496 (2023): 73–86.
|
| [26] |
Q. Wang, Z. Yang, Q. Li, W. Zhang, and P. Kang, “Lithium Prevents Glucocorticoid-Induced Osteonecrosis of the Femoral Head by Regulating Autophagy,” Journal of Cellular and Molecular Medicine 28, no. 10 (2024): e18385.
|
| [27] |
C. Chen, B. Wang, X. Zhao, et al., “Lithium Promotes Osteogenesis via Rab11a-Facilitated Exosomal Wnt10a Secretion and β-Catenin Signaling Activation,” ACS Applied Materials & Interfaces 16, no. 24 (2024): 30793–30809.
|
| [28] |
Y. Zhendong, C. Changjun, H. Haocheng, et al., “Regulation of Macrophage Polarization and Pyroptosis by 4-Methylcatechol Alleviates Collagen-Induced Arthritis via Nrf2/HO-1 and NF-κB/NLRP3 Signaling Pathways,” International Immunopharmacology 146 (2025): 113855.
|
| [29] |
C. Chen, S. Wang, J. Chen, et al., “Escin Suppresses HMGB1-Induced Overexpression of Aquaporin-1 and Increased Permeability in Endothelial Cells,” FEBS Open Bio 9, no. 5 (2019): 891–900.
|
| [30] |
H. Luo, J. Wei, S. Wu, Q. Zheng, X. Lin, and P. Chen, “Elucidating the Role of the GC/GR/GLUT1 Axis in Steroid-Induced Osteonecrosis of the Femoral Head: A Proteomic Approach,” Bone 183 (2024): 117074.
|
| [31] |
L. W. Zheng, C. N. Lan, Y. Kong, L. H. Liu, Y. M. Fan, and C. J. Zhang, “Exosomal miR-150 Derived From BMSCs Inhibits TNF-α-Mediated Osteoblast Apoptosis in Osteonecrosis of the Femoral Head by GREM1/NF-κB Signaling,” Regenerative Medicine 17, no. 10 (2022): 739–753.
|
| [32] |
A. Pinto, D. T. Juniper, M. Sanil, et al., “Supranutritional Selenium Induces Alterations in Molecular Targets Related to Energy Metabolism in Skeletal Muscle and Visceral Adipose Tissue of Pigs,” Journal of Inorganic Biochemistry 114 (2012): 47–54.
|
| [33] |
T. H. Kim, S. C. Bae, S. H. Lee, S. Y. Kim, and S. H. Baek, “Association of Complement Receptor 2 Gene Polymorphisms With Susceptibility to Osteonecrosis of the Femoral Head in Systemic Lupus Erythematosus,” BioMed Research International 2016 (2016): 9208035.
|
| [34] |
D. Wang, Y. Liu, D. Tang, et al., “Induction of PI3K/Akt-Mediated Apoptosis in Osteoclasts Is a Key Approach for Buxue Tongluo Pills to Treat Osteonecrosis of the Femoral Head,” Frontiers in Pharmacology 12 (2021): 729909.
|
| [35] |
J. Ma, M. Shen, D. Yue, W. Wang, F. Gao, and B. Wang, “Extracellular Vesicles From BMSCs Prevent Glucocorticoid-Induced BMECs Injury by Regulating Autophagy via the PI3K/Akt/mTOR Pathway,” Cells 11, no. 13 (2022): 2104.
|
| [36] |
X. Zhao, Y. Fang, X. Wang, et al., “Knockdown of Ski Decreases Osteosarcoma Cell Proliferation and Migration by Suppressing the PI3K/Akt Signaling Pathway,” International Journal of Oncology 56, no. 1 (2020): 206–218.
|
| [37] |
S. Deng, G. Dai, S. Chen, et al., “Dexamethasone Induces Osteoblast Apoptosis Through ROS-PI3K/AKT/GSK3β Signaling Pathway,” Biomedicine & Pharmacotherapy 110 (2019): 602–608.
|
| [38] |
C. J. Chen, X. Zhao, J. W. Zhao, et al., “Osteoblastic Bone Reaction Developing During Treatment With Sintilimab and Bevacizumab in a Patient With KRAS(G12V)-Mutant Lung Adenocarcinoma,” World Journal of Oncology 14, no. 6 (2023): 580–583.
|
| [39] |
B. Guo, W. Zhang, S. Xu, J. Lou, S. Wang, and X. Men, “GSK-3β Mediates Dexamethasone-Induced Pancreatic β Cell Apoptosis,” Life Sciences 144 (2016): 1–7.
|
| [40] |
S. Deng, Z. G. Nie, P. J. Peng, et al., “Decrease of GSK3β Ser-9 Phosphorylation Induced Osteoblast Apoptosis in Rat Osteoarthritis Model,” Current Medical Science 39, no. 1 (2019): 75–80.
|
| [41] |
C. Li, P. Yang, B. Liu, et al., “Prednisolone Induces Osteocytes Apoptosis by Promoting Notum Expression and Inhibiting PI3K/AKT/GSK3β/β-Catenin Pathway,” Journal of Molecular Histology 52, no. 5 (2021): 1081–1095.
|
| [42] |
Y. Gao, C. Chen, R. Liu, Z. Zhang, X. Zhao, and H. Ma, “Research Progress of Connexin 43 Mediated Gap Junction Communication Regulating Bone Metabolism in Glucocorticoid-Induced Osteonecrosis of the Femoral Head,” Experimental Cell Research 449, no. 1 (2025): 114598.
|
| [43] |
L. Xu, J. Wu, Y. Yu, et al., “Dok5 Regulates Proliferation and Differentiation of Osteoblast via Canonical Wnt/β-Catenin Signaling,” Journal of Musculoskeletal & Neuronal Interactions 22, no. 1 (2022): 113–122.
|
| [44] |
Y. Liu, L. Zhao, X. He, et al., “Jintiange Proteins Promote Osteogenesis and Inhibit Apoptosis of Osteoblasts by Enhancing Autophagy via PI3K/AKT and ER Stress Pathways,” Journal of Ethnopharmacology 311 (2023): 116399.
|
| [45] |
J. Y. Sun, Y. J. Hou, X. Y. Fu, et al., “Selenium-Containing Protein From Selenium-Enriched Spirulina Platensis Attenuates Cisplatin-Induced Apoptosis in MC3T3-E1 Mouse Preosteoblast by Inhibiting Mitochondrial Dysfunction and ROS-Mediated Oxidative Damage,” Frontiers in Physiology 9 (2018): 1907.
|
| [46] |
X. Wei, Z. Zhang, L. Wang, et al., “Enhancing Osteoblast Proliferation and Bone Regeneration by Poly (Amino Acid)/selenium-Doped Hydroxyapatite,” Biomedical Materials 19, no. 3 (2024): ad38ac.
|
| [47] |
S. Poleboina, V. G. Sheth, N. Sharma, P. Sihota, N. Kumar, and K. Tikoo, “Selenium Nanoparticles Stimulate Osteoblast Differentiation via BMP-2/MAPKs/β-Catenin Pathway in Diabetic Osteoporosis,” Nanomedicine (London, England) 17, no. 9 (2022): 607–625.
|
| [48] |
J. Hou, Y. Tamura, H. Y. Lu, et al., “An in Vitro Evaluation of Selenium Nanoparticles on Osteoblastic Differentiation and Antimicrobial Properties Against Porphyromonas gingivalis,” Nanomaterials (Basel) 12, no. 11 (2022): 1850.
|
| [49] |
T. Qi, Y. Yan, W. Qi, W. Chen, and H. Yang, “Hip Joint-Preserving Strategies for Treating Osteonecrosis of the Femoral Head: From Nonoperative to Operative Procedures,” Journal of Orthopaedic Translation 51 (2025): 256–277.
|
| [50] |
J. Zhao, W. He, H. Zheng, R. Zhang, and H. Yang, “Bone Regeneration and Angiogenesis by co-Transplantation of Angiotensin II-Pretreated Mesenchymal Stem Cells and Endothelial Cells in Early Steroid-Induced Osteonecrosis of the Femoral Head,” Cell Transplantation 31 (2022): 9636897221086965.
|
| [51] |
X. N. Li, L. Lin, X. W. Li, et al., “BSA-Stabilized Selenium Nanoparticles Ameliorate Intracerebral Hemorrhage's-Like Pathology by Inhibiting Ferroptosis-Mediated Neurotoxicology via Nrf2/GPX4 Axis Activation,” Redox Biology 75 (2024): 103268.
|
RIGHTS & PERMISSIONS
2025 The Author(s). Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.
PDF
