Ebselen rescues oxidative-stress-suppressed osteogenic differentiation of bone-marrow-derived mesenchymal stem cells via an antioxidant effect and the PI3K/Akt pathway

Background: Patients with metabolic bone diseases often have high risk of titanium implant failure due to compromised bone regeneration ability. Clinical evidence indicates that the poor osteogenic ability is partly because of excessive oxidative stress. To date, specific treatments for these patients are urgently needed. Ebselen, a non-toxic organoselenium compound, is reported to be a potent antioxidant agent. In this study, we hypothesized that ebselen exerted protective effects on osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress.

Methods: BMSCs were isolated from SD rats, and their morphology and multiple differentiation abilities were characterized. Proliferation rates of BMSCs treated with different concentrations of ebselen were analyzed. Then BMSCs were pretreated by hydrogen peroxide (H₂O₂), after which ebselen at different concentrations (0, 1, 5, 10 μM) was added, Alkaline Phosphatase (ALP) activity, mineralization and osteogenic-related protein levels were evaluated and an optimum concentration of ebselen was selected. Subsequently, intracellular Reactive Oxygen Species (ROS) generation and the role of the PI3K/Akt pathway were also investigated.

Results: Ebselen within a proper range could promote the proliferation of BMSCs. H₂O₂-induced oxidative stress suppressed osteogenic differentiation of BMSCs, which was verified by the decrease in ALP activity, calcium deposition, Runx2 and β-catenin expression. However, ebselen could alleviate osteogenic dysfunction of BMSCs. We also observed that ebselen reduced ROS accumulation in H₂O₂-pretreated BMSCs. Moreover, the pro-osteogenic effects afforded by ebselen were almost abolished by the Akt Inhibitor.

Conclusion: We concluded that ebselen could attenuate osteogenic dysfunction of BMSCs induced by H₂O₂ through an antioxidant effect and the activation of the PI3K/Akt pathway, suggesting that ebselen has a potential therapeutic effect for patients with metabolic bone diseases.