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

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.

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.

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.

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