An injectable hydrogel-formulated inhibitor of prolyl-4-hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis

FASEB J. 2020 Oct;34(10):13726-13740. doi: 10.1096/fj.202001248R. Epub 2020 Aug 19.

Abstract

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.

Keywords: 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid; AMD3100; T regulatory cells; hypoxia-inducible factor 1α; osteogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Regeneration*
  • Cell Line
  • Cells, Cultured
  • Cytokines / metabolism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Forkhead Transcription Factors / metabolism
  • Gingiva / metabolism
  • Humans
  • Hydrogels / administration & dosage
  • Hydrogels / chemistry
  • Hydrogels / therapeutic use*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteogenesis
  • Periodontitis / drug therapy*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / physiology

Substances

  • Cytokines
  • Enzyme Inhibitors
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hif1a protein, mouse
  • Hydrogels
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Hypoxia-Inducible Factor-Proline Dioxygenases