Metformin reverses impaired osteogenesis due to hyperglycemia-induced neutrophil extracellular traps formation

Diabetic patients suffer from delayed fracture healing and impaired osteogenic function, but the underlying pathophysiological mechanisms are not fully understood. Neutrophil extracellular traps (NETs) formed by neutrophils in high glucose microenvironments affect the healing of wounds and other tissues. Some evidence supports that NETs may inhibit osteogenic processes in the microenvironment through sustained inflammatory activation. In this study, we observed that high glucose-induced NETs led to sustained inflammatory activation of macrophages. Pro-inflammatory NETs inhibited the osteogenic function of osteoblasts in vitro. A bone defect healing model based on diabetic rat animal models confirmed that bone healing was impaired in a high glucose environment, but this process could be reversed by DNase I, a NETs clearance agent. More importantly, the classic hypoglycemic drug metformin had a similar antagonistic effect as DNase I and could reverse the inhibitory effect of NETs on osteogenesis in a high-glucose environment. In summary, we found that NETs formation induced by high glucose microenvironment is a potential cause of osteogenic dysfunction in diabetic patients, and metformin can reverse this osteogenic disadvantage.