Calcium silicate induces mitophagy-mediated metabolic shifts toward oxidative phosphorylation in BMSCs to facilitate osteogenesis and bone regeneration.

Calcium silicate (CS)-based bioactive materials were widely utilized to promote the therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) in bone tissue engineering. The activation of numerous classic bone formation modulators, including the BMP, Wnt, and MAPK/ERK signaling pathways, contributes to the CS-induced osteogenesis of BMSCs. Mitochondrial metabolic patterns have emerged as key contributors to the osteogenic differentiation of mesenchymal stem cells. However, whether CS affects the mitochondrial metabolic profiles of BMSCs is mostly unclear. Herein, we showed that CS induced the osteogenic differentiation of human BMSCs (hBMSCs) mainly via silicon (Si) ion release. Moreover, CS-stimulated hBMSCs underwent metabolic reprogramming accompanied by increased mitochondrial oxidative phosphorylation (OXPHOS) activity. The inhibition of OXPHOS hindered the CS-induced osteogenic differentiation of hBMSCs and bone regeneration, indicating that CS-induced OXPHOS mediated the observed increase in osteogenesis. Mechanistically, CS induced mitophagy and autophagic flux by increasing the formation of autolysosomes and lysosomal degradation to eliminate dysfunctional mitochondria and mitochondrial reactive oxygen species production, leading to enhanced OXPHOS and osteogenesis in hBMSCs. Furthermore, CS promoted mitochondrial fusion in hBMSCs, which may contribute to OXPHOS activation. Our investigation reveals a previously unclear function of CS in regulating the osteogenesis of BMSCs by inducing mitophagy-mediated metabolic shifts toward OXPHOS.