FOXG1 promotes osteogenesis of bone marrow-derived mesenchymal stem cells by activating autophagy through regulating USP14.

The osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) is key for bone formation, and its imbalance leads to osteoporosis. Forkhead Box Protein G1 (FOXG1) is associated with osteogenesis, however, the effect of FOXG1 on osteogenesis of BMSCs and ovariectomy (OVX)-induced bone loss is unknown. In our study, FOXG1 expression in BMSCs increases after osteogenic induction. FOXG1 overexpression significantly increases osteoblast marker expression ALP activity, and calcium deposition, while the opposite results are observed in FOXG1 knockdown BMSCs, suggesting that FOXG1 promotes osteogenic differentiation. Additionally, autophagy promotes the differentiation process in BMSCs. We find that FOXG1 induces autophagy, and osteogenic differentiation is blocked via inhibiting FOXG1-caused autophagy, indicating that FOXG1 accelerates osteogenic differentiation via inducing autophagy. Eight-week-old female C57BL/6J mice are used in OVX models, FOXG1 overexpression decreases bone loss by increasing bone formation. Moreover, FOXG1 overexpression suppresses osteoclast differentiation. Mechanically, FOXG1 transcriptionally represses ubiquitin-specific protease14 (USP14) via binding to the USP14 promoter. USP14 overexpression prevents the promoting effect of FOXG1 on osteogenic differentiation in BMSCs. Therefore, our findings suggest that FOXG1 promotes BMSC osteogenic differentiation and inhibits osteoclast differentiation, eventually blocking OVX-induced bone loss, which may provide a promising approach for osteoporosis treatment.