Tazarotene ameliorates steroid-induced osteonecrosis of the femoral head by activating autophagy.

BACKGROUND

Steroid-induced osteonecrosis of the femoral head (SIONFH) is a debilitating condition characterized by lipid accumulation and bone structural collapse. A key pathogenic mechanism involves downregulated osteogenesis and upregulated adipogenesis of bone marrow mesenchymal stem cells (BMSCs). Autophagy has been implicated in lipid metabolism and bone homeostasis. This study investigated whether activating autophagy could ameliorate SIONFH.

METHODS

Lipid droplet based high-throughput screening of an active compound library was performed on dexamethasone (DEX)-treated rat BMSCs. Further evaluations based on rat SIONFH model including bone microstructure, histological analysis and serum marker, serum biochemical analysis. Western blot, flow cytometry for apoptosis, and molecular docking to predict target interactions.

RESULTS

Retinoid agonist Tazarotene effectively reduced lipid droplet accumulation in BMSCs by activating autophagy and attenuating apoptosis. Tazarotene restored the osteogenic-adipogenic differentiation balance. Mechanistically, network pharmacology and molecular docking suggested mTOR as a potential target. In the SIONFH rat model, tazarotene treatment significantly improved femoral head microstructure, reduced empty lacunae, and promoted osteogenic markers while suppressing adipogenic markers.

CONCLUSION

Tazarotene ameliorates SIONFH by activating autophagy in BMSCs. These findings highlight tazarotene's potential as a novel therapeutic strategy for SIONFH.