Deficiencia de S100a9 en neutrófilos protege contra la pérdida ósea periodontal

Periodontitis is an inflammatory disease driven by microbial dysbiosis, characterized by immune dysregulation and alveolar bone resorption. Although upregulation of S100A8/A9 levels was found in human periodontitis, its mechanism of regulating osteoimmunological homeostasis during periodontitis progression remains elusive. To investigate this, we constructed a ligature-induced periodontitis model using S100a9 knockout mice. Further studies showed that S100a9 knockout mice exhibited impaired neutrophil extracellular trap (NET) formation and ameliorated bone resorption. Mechanistic studies demonstrated that S100a9 deficiency inhibits neutrophil autophagy, resulting in diminished NET formation (NETosis), which consequently suppressed osteoclast differentiation. This effect was reversible in S100a9 deficiency mice upon rapamycin-induced autophagy restoration. Therapeutic intervention with the S100A9-specific inhibitor tasquinimod effectively inhibited osteoclastic differentiation of macrophages and mitigated bone loss. In conclusion, our findings reveal the mechanism by which S100A9 regulates osteoclast differentiation via NETosis, providing insights into osteoimmunological regulation in the pathogenesis of periodontitis.