Neutrophil extracellular traps promote bone loss in type 1 diabetes via suppression of the FN1-PI3K/Akt signaling axis.

Diabetes-induced osteoporosis (DOP) is a severe complication of type 1 diabetes mellitus (T1D), characterized by impaired bone formation. However, the underlying mechanisms remain poorly understood. Using a streptozotocin (STZ)-induced T1D mouse model, we observed pronounced trabecular bone loss, demonstrated by micro-CT and histological analyses. Concurrently, diabetic bone marrow showed a marked accumulation of neutrophil extracellular traps (NETs), as confirmed by immunofluorescence and Western blot for MPO and citrullinated histone H3 (CitH3). Therapeutic degradation of NETs with DNase I significantly restored trabecular bone microarchitecture and enhanced osteoblast activity, evidenced by increased osteocalcin (OCN) and RUNX2 expression. In vitro, NETs impaired osteogenic differentiation of MC3T3-E1 cells, suppressing ALP activity and downregulating osteogenic markers OPN and RUNX2-effects that were reversed by DNase I. Transcriptomic profiling revealed that NETs downregulated fibronectin 1 (FN1), disrupting PI3K/Akt signaling and ECM-receptor interaction pathways. Restoration of FN1 expression, either in vivo via DNase I or in vitro via exogenous supplementation, rescued osteogenic capacity. Furthermore, inhibition of PI3K signaling with LY294002 abrogated the osteoprotective effects of FN1, confirming that the FN1-PI3K/Akt axis mediates NETs-induced osteogenic suppression. These findings identify NETs as critical mediators of diabetic bone loss through FN1 downregulation and suppression of PI3K/Akt signaling. Targeting NETs or restoring FN1-PI3K/Akt signaling may therefore represent promising therapeutic strategies for diabetes-associated osteoporosis.