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.

转录因子 Foxk1 可以调节细胞增殖、分化、代谢，促进骨骼肌再生和心脏发生。然而，Foxk1 在骨形成中的作用尚不清楚。在这里，我们发现 Foxk1 在老年小鼠和骨质疏松症患者的骨组织中表达降低。敲低原代小鼠颅骨成骨细胞中的 Foxk1 抑制成骨细胞分化和增殖。小鼠前成骨细胞和成熟成骨细胞中 Foxk1 的条件敲除表现出由于骨形成减少而导致的骨量和机械强度降低。从机制上讲，我们通过 CUT&Tag 分析鉴定出 Foxk1 靶向糖酵解酶许多基因的启动子区域。原代小鼠颅骨成骨细胞中缺乏 Foxk1 导致需氧糖酵解减少。2DG 对糖酵解的抑制阻碍了 Foxk1 过表达诱导的成骨细胞分化和增殖。最后，在成骨细胞前特异性 osterix 启动子的驱动下，Foxk1 在成骨前细胞中的特异性过表达增加了老年小鼠的骨量和骨机械强度，这可以通过抑制糖酵解来抑制。综上所述，这些发现揭示了 Foxk1 在成骨细胞代谢调节和骨形成刺激中起着至关重要的作用，为预防与年龄相关的骨质流失提供了一种有前途的方法。