MC3T3-E1 cells lead to bone loss in Staphylococcus aureus osteomyelitis through oxeiptosis pathway

Bone loss is a significant complication of Staphylococcus aureus osteomyelitis, for which there is currently no efficacious treatment despite research indicating the involvement of various mechanisms in bone loss during bone infections. Oxeiptosis, a caspase independent form of cell death induced by oxidative stress, has been implicated in pathogen elimination. Nevertheless, the role of oxeiptosis in the extinction of osteoblasts during S. aureus infection remains uncertain. In the current investigation, preliminary evidence suggests the existence of alternative mechanisms of cell demise beyond the established pathways of apoptosis and necrosis following S. aureus infection in osteoblasts. Moreover, our findings indicate that dephosphorylation of AIFM1 at Ser116 occurs during S. aureus infection in osteoblasts, ultimately resulting in osteoblast death. Additionally, KEAP1 and PGAM5, situated upstream of AIFM1 in this cascade, are implicated in the process of osteoblast death. Our study demonstrates that the KEAP1-PGAM5-AIFM1 signaling pathway is implicated in S. aureus-induced osteoblast death through the depletion of KEAP1 and PGAM5. This suggests that infection through the oxeiptosis pathway may contribute to osteoblast death and subsequent bone loss in individuals with osteomyelitis.