Double-edged effects and mechanisms of Zn microenvironments on osteogenic activity of BMSCs: osteogenic differentiation or apoptosis.

Zinc-incorporated biomaterials show promoting effects on osteogenesis; however, excessive zinc ions lead to cytotoxic reactions and also have other adverse effects. Therefore, the double-edged effects of Zn microenvironments on osteogenesis may become critical issues for new material development. This study systematically investigated the bidirectional influences of diverse Zn microenvironments on the cell adhesion, proliferation, osteogenic differentiation and apoptosis of rBMSCs. Furthermore, the mechanisms of zinc-induced osteogenic differentiation of rBMSCs and of cell apoptosis induced by high concentration of Zn were both discussed in detail. The results indicated that the Zn microenvironments of 2 μg mL and 5 μg mL effectively improved the initial adhesion and proliferation of rBMSCs, while that of 15 μg mL had exactly the opposite effect. More importantly, the suitable Zn microenvironments (2 μg mL and 5 μg mL) moderately increased the intracellular Zn concentration by regulating zinc transportation, and then activated the MAPK/ERK signaling pathway to induce the osteogenic differentiation of rBMSCs. In contrast, the high Zn concentration (15 μg mL) not only inhibited the osteogenic differentiation of rBMSCs by damaging intracellular zinc homeostasis, but also induced rBMSC apoptosis by enhancing intracellular ROS generation. The current study clarified the double-edged effects of Zn microenvironments on the osteogenic properties of rBMSCs and the related mechanisms, and may provide valuable guidance for optimizing the design of zinc-doped biomaterials and zinc-based alloys.