Targeting the neuropilin 1/interferon γ axis restores glucocorticoid-suppressed T cell function and rescues bone formation to prevent steroid-induced osteonecrosis.

AIMS: Immune cells exert influence on skeletal homeostasis, and re-establishing metabolic equilibrium is central to the management of steroid-induced osteonecrosis of the femoral head (SIONFH). However, the osteoimmune mechanisms underpinning this pathology remain largely under-researched. This study aimed to delineate these mechanisms, thereby informing early therapeutic strategies to restore bone homeostasis.

METHODS

We identified the key immune cell subsets associated with SIONFH, and investigated their upstream regulatory factors and downstream effector molecules by integrating multiomics analyses (samples derived from human peripheral blood, femoral head tissues, and rat peripheral blood), mining of the GSE123568 dataset, and performing in vivo and in vitro experiments.

RESULTS

Clinical transcriptomics revealed enrichment of immune-related pathways, with ssGSEA consistently highlighting activated CD8+ T cells and Th1 cells. Correlation analyses demonstrated a stronger association between T cells and osteoblasts than osteoclasts (r = 0.8728 vs r = -0.065). Staphylococcal enterotoxin C2 (sec2) activated T cells both in vitro and in vivo, thereby augmenting osteogenic markers, enhancing bone marrow stromal cell (BMSC) differentiation, and elevating T cell-derived interferon gamma (IFNγ). Mechanistically, IFNγ facilitated signal transducer and activator of transcription 1 (STAT1)-runt-related transcription factor 2 (Runx2) dissociation and Runx2 nuclear translocation, thereby potentiating osteogenesis. Multiomics and functional studies identified neuropilin 1 (NRP1) as a critical IFNγ/T cell-associated protein, downregulated by staphylococcal enterotoxin C2 (sec2). Pharmacological activation of NRP1 with certepetide validated its role in modulating IFNγ secretion and downstream signalling. Glucocorticoids suppress IFNγ production in T cells and weaken NRP1/IFNγ-driven osteogenic differentiation. Ultimately, sec2 reshaped antigen-presenting cell-mediated regulation of the T cell-NRP1/IFNγ axis, promoting bone formation and mitigating SIONFH.

CONCLUSION

Glucocorticoids suppress T cell-derived IFNγ via NRP1 upregulation, thereby impairing Runx2 nuclear translocation and BMSC osteogenesis. Sec2 counteracts this cascade through antigen-presenting cell modulation, restoring the NRP1/IFNγ axis to preserve femoral head integrity.