Glucocorticoid-induced osteoporosis (GIOP) remains a major clinical challenge, affecting up to half of patients receiving long-term glucocorticoid therapy. Excessive oxidative stress and impaired osteoblast differentiation are central drivers of bone loss in this condition, yet the molecular regulators linking redox imbalance to osteogenic dysfunction are incompletely understood.
This new study, published in Genes & Diseases, by researchers from The Fourth Military Medical University, Affiliated Hospital of Zunyi Medical University, Global Institute of Software Technology and Honghui Hospital of Xi'an Jiaotong University identifies TP53-induced glycolysis and apoptosis regulator (TIGAR) as a critical protective factor that preserves osteoblast function and mitigates GIOP through activation of the autophagy–Nrf2–ROS axis.
Using both in vitro and in vivo models, the researchers demonstrate that dexamethasone (Dex) suppresses TIGAR expression in bone tissue and bone marrow mesenchymal stem cells (BMSCs), coinciding with reduced bone mineral density, trabecular deterioration, and impaired osteogenic differentiation. Restoration of TIGAR expression—either through plasmid-mediated overexpression in BMSCs or in TIGAR-transgenic mice—significantly reversed Dex-induced suppression of osteogenic markers, including Runx2 and Sp7, and restored alkaline phosphatase activity and mineralized nodule formation.
Mechanistically, TIGAR overexpression markedly reduced intracellular reactive oxygen species (ROS) accumulation and apoptosis in Dex-treated osteoblasts. This antioxidant effect was accompanied by restoration of the NADPH/NADP⁺ ratio and glutathione levels, along with upregulation of antioxidant enzymes such as Sod1, Gpx1, and Cat. These findings establish TIGAR as a key modulator of redox balance during glucocorticoid exposure.
Importantly, the study reveals that TIGAR activates nuclear factor erythroid 2–related factor 2 (Nrf2), a master regulator of antioxidant defense. Dex suppressed Nrf2 expression and nuclear translocation, whereas TIGAR overexpression restored Nrf2 activation. Pharmacological inhibition of Nrf2 abrogated TIGAR-mediated ROS reduction, confirming that Nrf2 is required for TIGAR's protective effects.
Further investigation uncovered an autophagy-dependent mechanism underlying Nrf2 activation. TIGAR enhanced autophagic flux, promoting degradation of Keap1—the cytoplasmic inhibitor of Nrf2—and facilitating Nrf2 nuclear translocation. Blocking autophagy with chloroquine prevented Keap1 degradation, suppressed Nrf2 activation, and eliminated TIGAR's antioxidant benefits. These data define an integrated autophagy–Keap1–Nrf2 signaling cascade through which TIGAR alleviates oxidative stress and preserves osteoblast viability.
In vivo, TIGAR-transgenic mice exhibited significant resistance to Dex-induced bone loss, with improved trabecular architecture and osteogenic activity compared to wild-type controls.
Collectively, this study identifies TIGAR as a central regulator of osteoblast redox homeostasis and bone formation under glucocorticoid stress. By activating autophagy-dependent Nrf2 signaling, TIGAR mitigates oxidative damage and apoptosis, highlighting its potential as a therapeutic target for glucocorticoid-induced osteoporosis.
Reference
Title of Original Paper: TIGAR promotes osteogenic differentiation and ameliorates glucocorticoid-induced osteoporosis via autophagy-Nrf2-ROS axis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101735
