High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein that is secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 and analysis indicated that HMGB1, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α-induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils, and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative reverse transcription-PCR (RT-PCR), and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and the anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently suppressing the progression of periodontitis.
The hypoxia‐inducible factor 1α (HIF‐1α) is critically involved in tissue regeneration. Hence, the pharmacological prevention of HIF‐1α degradation by prolyl hydroxylase (PHD) under normoxic conditions is emerging as a promising option in regenerative medicine. Using a mouse model of ligature‐induced periodontitis and resolution, we tested the ability of an injectable hydrogel‐formulated PHD inhibitor, 1,4‐dihydrophenonthrolin‐4‐one‐3‐carboxylic acid (1,4‐DPCA/hydrogel), to promote regeneration of alveolar bone lost owing to experimental periodontitis. Mice injected subcutaneously with 1,4‐DPCA/hydrogel at the onset of periodontitis resolution displayed significantly increased gingival HIF‐1α protein levels and bone regeneration, as compared to mice treated with vehicle control. The 1,4‐DPCA/hydrogel‐induced increase in bone regeneration was associated with elevated expression of osteogenic genes, decreased expression of pro‐inflammatory cytokine genes, and increased abundance of FOXP3+ T regulatory (Treg) cells in the periodontal tissue. The enhancing effect of 1,4‐DPCA/hydrogel on Treg cell accumulation and bone regeneration was reversed by AMD3100, an antagonist of the chemokine receptor CXCR4 that mediates Treg cell recruitment. In conclusion, the administration of 1,4‐DPCA/hydrogel at the onset of periodontitis resolution promotes CXCR4‐dependent accumulation of Treg cells and alveolar bone regeneration, suggesting a novel approach for regaining bone lost due to periodontitis.
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