Foxk1 promotes bone formation through inducing aerobic glycolysis.

Transcription factor Foxk1 can regulate cell proliferation, differentiation, metabolism, and promote skeletal muscle regeneration and cardiogenesis. However, the roles of Foxk1 in bone formation is unknown. Here, we found that Foxk1 expression decreased in the bone tissue of aged mice and osteoporosis patients. Knockdown of Foxk1 in primary murine calvarial osteoblasts suppressed osteoblast differentiation and proliferation. Conditional knockout of Foxk1 in preosteoblasts and mature osteoblasts in mice exhibited decreased bone mass and mechanical strength due to reduced bone formation. Mechanistically, we identified Foxk1 targeted the promoter region of many genes of glycolytic enzyme by CUT&Tag analysis. Lacking of Foxk1 in primary murine calvarial osteoblasts resulted in reducing aerobic glycolysis. Inhibition of glycolysis by 2DG hindered osteoblast differentiation and proliferation induced by Foxk1 overexpression. Finally, specific overexpression of Foxk1 in preosteoblasts, driven by a preosteoblast specific osterix promoter, increased bone mass and bone mechanical strength of aged mice, which could be suppressed by inhibiting glycolysis. In summary, these findings reveal that Foxk1 plays a vital role in the osteoblast metabolism regulation and bone formation stimulation, offering a promising approach for preventing age-related bone loss.