An injectable hydrogel-formulated inhibitor of prolyl-4-hydroxylase promotes T regulatory cell recruitment and enhances alveolar bone regeneration during resolution of experimental periodontitis
| Autor: | Hidetaka Ideguchi, Ellen Heber-Katz, Xiaofei Li, Tetsuhiro Kajikawa, Phillip B. Messersmith, Jing Cheng, Triantafyllos Chavakis, George Hajishengallis, Kosuke Nagai |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Bone Regeneration Physiology T-Lymphocytes Medical Physiology Gingiva Inbred C57BL Regenerative Medicine Biochemistry CXCR4 Regenerative medicine T-Lymphocytes Regulatory Chemokine receptor Mice 0302 clinical medicine Osteogenesis Enzyme Inhibitors Cells Cultured Cultured Chemistry FOXP3 Forkhead Transcription Factors Hydrogels Regulatory 4-dihydrophenonthrolin-4-one-3-carboxylic acid Cytokines Female Hypoxia-Inducible Factor 1 Biotechnology Biochemistry & Molecular Biology Cells T regulatory cells 1.1 Normal biological development and functioning alpha Subunit Article AMD3100 osteogenesis Cell Line Hypoxia-Inducible Factor-Proline Dioxygenases 03 medical and health sciences Underpinning research Genetics medicine Animals Humans Dental/Oral and Craniofacial Disease Bone regeneration Periodontitis Molecular Biology hypoxia-inducible factor 1α Dental alveolus Regeneration (biology) medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit Mice Inbred C57BL 030104 developmental biology Musculoskeletal Cancer research hypoxia-inducible factor 1 alpha Biochemistry and Cell Biology 030217 neurology & neurosurgery |
| Zdroj: | FASEB J FASEB journal : official publication of the Federation of American Societies for Experimental Biology, vol 34, iss 10 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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