BACKGROUND AIMS: Osteoporosis (OP) is a common disease of aging, which is closely related to the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). DNA damage, as a senescence-associated secretory phenotype (SASP), plays an important role in aging diseases including OP. GIT2 has been identified as a DNA repair gene and alleviates aging-related phenotypes. However, the relationship between GIT2 and osteogenic differentiation of BMSCs remains unclear. METHODS: Here, we used bioinformatics analysis to identify the gene GIT2, which is closely related to aging, OP and DNA damage, and its downstream targets. Then, H RESULTS: Our results showed that GTI2 and TRAF3 were positively correlated with OP-related markers. On the one hand, GIT2 could inhibit the activation of both canonical and non-canonical NF-κB signaling pathways by positively regulating TRAF3. On the other hand, GIT2 could directly bind to P65, a component of the classical NF-κB signaling pathway, and P52, a component of the non-classical NF-κB signaling pathway, to inhibit their activation, improve DNA damage repair, alleviate cell senescence, and further promote osteogenic differentiation of BMSCs. CONCLUSIONS: In summary, the present study demonstrates that GIT2 plays a crucial regulatory role in promoting osteogenic differentiation of BMSCs, which provides new ideas for the prevention and treatment of OP and other aging-related diseases.