Periodontitis Leads to Systemic Bone Loss through Neutrophil Reprogramming

Periodontitis is a chronic oral inflammatory disease characterized by alveolar bone loss. Other diseases, such as osteoporosis, cardiovascular disease, and diabetes, can exacerbate its progression. These chronic diseases also have systemic effects that vary in frequency in men and women. Thus, this study sought to determine if periodontitis induced sex-specific changes in long bones. Periodontitis was induced by tying a 5-0 silk suture around the second maxillary molar of 6- to 8-wk-old male and female C57BL/6J mice. Ligatures were left in place for 7 d or 21 d, and the tibia was subsequently collected for characterization using micro-computed tomography, flow cytometry, and proteomics analysis. Female mice exhibited sustained trabecular and cortical bone loss through day 21, whereas males recovered from any bone loss observed at day 7. Flow cytometry and proteomics analysis indicated that an increased neutrophil response contributes to this bone loss by upregulating pathways associated with neutrophil extracellular trap (NET) formation and reactive oxygen species production. Eliminating NET generation using a Padi4-deficient mouse eliminated the bone loss phenotype during periodontitis. This study suggests that the neutrophil-driven pattern of bone loss observed in female mice, as well as the higher prevalence of osteoporosis in women, may highlight a potential mechanism by which periodontitis exacerbates systemic bone loss.