GDNF Maintains Mitochondrial Homeostasis and Inhibits Ferroptosis to Improve Osteogenic Function in Osteoporosis

Osteoporosis is a metabolic bone disease characterized by reduced bone mass and deterioration of bone microarchitecture, in which impaired osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) represents a central pathological mechanism. In recent years, ferroptosis, a newly recognized form of regulated cell death, has been demonstrated to play an important role in the initiation and progression of osteoporosis. Mitochondrial dysfunction can exacerbate oxidative stress and disrupt iron metabolism, thereby triggering ferroptosis in BMSCs and ultimately inhibiting osteogenic differentiation. The present study aimed to identify and validate key genes associated with mitochondrial homeostasis and osteoporosis, with a particular focus on the role of glial cell line-derived neurotrophic factor (GDNF) in regulating mitochondrial function, suppressing ferroptosis, and promoting osteogenic differentiation of BMSCs. Gene expression data from normal human bone tissues and osteoporotic bone tissues were obtained from public transcriptomic datasets in the Gene Expression Omnibus (GEO) database. Through differential expression analysis, GDNF was identified as a candidate gene. In vitro experiments demonstrated that GDNF markedly improved mitochondrial membrane potential, reduced intracellular reactive oxygen species (ROS) levels, and restored GPX4 expression, thereby promoting osteogenic differentiation of BMSCs. Furthermore, animal experiments confirmed that GDNF intervention effectively increased bone mineral density and improved trabecular microarchitecture in ovariectomized (OVX) mice. In conclusion, this study identified GDNF may suppress ferroptosis by maintaining mitochondrial homeostasis in BMSCs, thereby enhancing osteogenic differentiation and alleviating osteoporosis, providing a potential theoretical basis for molecular targeted therapy in osteoporosis.