Oral administration of alpha-ketoglutarate partially ameliorates Cadmium-compromised BMSC mobilization and cranial bone repair

Abstract

Cadmium (Cd) is a widespread environmental heavy metal pollutant known to disrupt bone metabolism, causing significant health concerns. Cd exposure impairs osteogenesis in primary bone marrow-derived mesenchymal stem cells (BMSCs) through mechanisms involving oxidative stress and NF-κB inflammation signaling. However, the underlying effects and mechanisms by which Cd hampers bone defect repair remain largely unknown. Additionally, alpha-ketoglutarate (AKG) is a dietary supplement as an antioxidant to potentially improve healthy longevity. In this study, we used a rat model to investigate the toxicology mechanisms of Cd to suppress bone repair and identify orally administrated AKG as a potential therapeutic intervention. Herein, we demonstrated that Cd inhibited BMSC and vascular endothelial cell motility, markedly reducing lamellipodia formation and cell migration. Cd also disrupted cytoskeletal reorganization and cell adhesion in BMSCs. Moreover, our data indicated that Cd induced abnormal expression of RhoA protein and suppressed the Notch1 pathway. In vivo studies further revealed that Cd significantly impaired cranial bone defect repair, tissue healing, and the formation of new vascular structures. These findings suggested that Cd interfered with BMSC migration and homing to bone defect sites, obstructing bone repair and healing. Intriguingly, AKG partially restored Cd-impaired BMSC mobilization and exhibited partial efficacy in ameliorating cranial bone defect repair compromised by Cd. Our study uncovered a novel mechanism by which Cd exposure impeded bone repair and presented AKG administration as a potential approach to mitigate Cd-induced bone tissue damage. This work may broaden our current understanding of Cd-induced bone disorders.