Objective:To explore the molecular mechanism for bone mass loss caused by staphylococcus aureus infection.Methods:Thirty 8-week-old male C57BL/6 mice were randomly divided into 3 groups ( n=10): control, infection and infection+JAK inhibitor (JAKi) ones. The mice were killed 2 weeks later for sampling from the femur and tibia. Micro-CT reconstruction was performed for analyses of BV/TV, Tb.N, Tb.Th and Tb.Sp to detect changes in bone mass; OCN immunohistochemistry and Goldner's trichrome staining were used to quantify osteoblasts; TRAP staining was used to quantify osteoclasts; the GSE166522 data set was downloaded and analyzed to explore the relationships between staphylococcus aureus infection and bone cell senescence and JAK/STAT pathway. Senescence β-Galactosidase staining, Osterix and P16 immunofluorescence colocalization were used to observe the changes in number of senescent cells. Results:MicroCT results showed a statistically significant difference in the loss of cancellous bone in the target area in the infection group compared with the control group ( P<0.05). The results of osteocalcin immunohistochemistry and Goldner's trichrome staining indicated that the number of osteoblasts in the infection group was significantly reduced ( P<0.05). TRAP staining indicated no significant difference in the number of osteoclasts between the infection and control groups ( P>0.05). Bioinformatics analysis found that staphylococcus aureus infection caused bone cell senescence and the JAK/STAT pathway was activated after the infection. Senescence β-Galactosidase staining suggested that senescent cells increased in the infection group compared with the control group. The number of Osterix and P16 positive senescent osteoprogenitor cells in the infection group was increased significantly compared with the control group. The number of senescent osteoprogenitor cells in the infection+JAKi group was significantly reduced and the bone loss was partially reversed after treatment of JAK inhibitor, compared with the infection group. Conclusion:Staphylococcus aureus may induce osteoprogenitor cell senescence through the JAK/STAT pathway and eventually lead to bone mass loss.