Ferritin promotes monocyte osteoclastogenic differentiation to aggravate alveolar bone resorption in periodontitis.

BACKGROUND/PURPOSE: Alveolar bone resorption in periodontitis critically impairs masticatory function and tooth stability, yet the mechanistic drivers linking immune dysregulation to osteolytic pathology remain incompletely characterized. This study elucidates how ferritin-an inflammation responsive iron chaperone secreted by activated monocytes-orchestrates monocyte-to-osteoclast differentiation to exacerbate bone destruction in periodontitis.

MATERIALS AND

METHODS

Using a multidisciplinary approach, we combined: Immunohistochemical profiling of cluster of differentiation 68-positive (CD68+) cells and cluster of differentiation 4-positive (CD4+) cells in human periodontal tissues (periodontitis vs. healthy controls); Murine experimental periodontitis induced by maxillary molar ligation (8-week model); In vitro mechanistic studies where THP-1 monocytes (human acute monocytic leukemia cell line) primed with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) were analyzed for ferritin/receptor activator of nuclear factor-κB ligand (RANKL) secretion, and RAW264.7 pre-osteoclasts (murine macrophage-like cell line) were treated with apoferritin ± RANKL to assess proliferation, osteoclast differentiation, and osteolytic gene expression.

RESULTS

Inflamed periodontal tissues exhibited elevated CD68+ and CD4+ immune cells, reflecting heightened inflammatory activity. P. gingivalis-LPS stimulation increased ferritin and RANKL secretion in THP-1 cells. Mice with experimental periodontitis showed increased osteoclast density at alveolar bone surfaces. Apoferritin synergized with RANKL to enhance RAW264.7 proliferation, multinucleation, and expression of matrix metallopeptidase 9 (MMP-9), cathepsin K (CTSK), and tartrate-resistant acid phosphatase (TRAP) in a dose-dependent manner.

CONCLUSION

Ferritin and RANKL synergistically promote monocyte osteoclastogenesis, driving alveolar bone resorption in periodontitis. Targeting ferritin signaling may offer therapeutic potential to mitigate bone loss.