Dexras1 plays a crucial role in glucocorticoid-induced osteonecrosis of the femoral head by mediating imbalance between osteogenesis and adipogenesis.

The imbalance between osteogenesis and adipogenesis in the femoral head is a major pathogenic mechanism underlying glucocorticoid (GC)-induced osteonecrosis of the femoral head (GIONFH), yet its specific molecular pathogenesis remains elusive. Dexras1 has been reported to mediate GC-induced osteogenesis-adipogenesis imbalance in osteoporosis, but its functional role and related mechanisms in GIONFH remain unclear. Here, we first demonstrated that Dexras1 expression was upregulated in rat models of GIONFH. Using Dexras1-knockout (KO) rats, radiographic and histological assessments demonstrated that Dexras1 ablation attenuated the osteonecrosis severity and restored the osteogenesis-adipogenesis balance in the femoral head. Results from RT-PCR, western blotting, alkaline phosphatase staining, and Oil Red O staining showed that Dexras1 KO promoted osteogenesis while inhibiting adipogenesis in bone marrow mesenchymal stem cells (BMSCs), whereas Dexras1 overexpression exerted the opposite effects. Additionally, TUNEL, Cell Counting Kit-8, and flow cytometry assays revealed that Dexras1 had no impact on BMSC viability in the rat GIONFH model. Dihydroethidium (DHE) staining and superoxide dismutase (SOD) activity assays further confirmed that Dexras1 was not involved in GC-induced oxidative stress in the femoral head. Finally, we confirmed that the upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and downregulation of Wnt signaling pathways were potential mechanisms underlying Dexras1-mediated osteogenesis-adipogenesis imbalance by RNA sequencing and some in vitro experiments. Collectively, our results demonstrate that Dexras1 is critical for GIONFH development, as it mediates the imbalance between osteogenesis and adipogenesis.