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An injectable hydrogel‐formulated inhibitor of prolyl‐4‐hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis
Author(s) -
Nagai Kosuke,
Ideguchi Hidetaka,
Kajikawa Tetsuhiro,
Li Xiaofei,
Chavakis Triantafyllos,
Cheng Jing,
Messersmith Phillip B.,
HeberKatz Ellen,
Hajishengallis George
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001248r
Subject(s) - periodontitis , regeneration (biology) , dental alveolus , chemokine , microbiology and biotechnology , inflammation , foxp3 , stromal cell , chemistry , systemic administration , immunology , cancer research , medicine , biology , dentistry , immune system , in vivo
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.