Institution: | 1. Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, Giessen, Germany;2. Department of Periodontics, Faculty of Medicine, Justus Liebig University Giessen, Giessen, Germany
Contribution: Investigation (equal), Methodology (equal), Project administration (equal), Validation (equal), Writing - review & editing (equal);3. Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, Giessen, Germany
Contribution: Methodology (equal);4. Department of Orthodontics, Faculty of Medicine, Justus Liebig University Giessen, Giessen, Germany
Contribution: Formal analysis (equal), Funding acquisition (equal), Methodology (equal), Project administration (equal), Supervision (equal), Validation (equal), Writing - review & editing (equal) |
Abstract: | Hypoxia-induced apoptosis of cementoblasts (OCCM-30) may be harmful to orthodontic treatment. Hypoxia-inducible factor 1-alpha (HIF-1α) mediates the biological effects during hypoxia. Little is known about the survival mechanism capable to counteract cementoblast apoptosis. We aimed to investigate the potential roles of HIF-1α, as well as the protein-protein interactions with ERK1/2, using an in-vitro model of chemical-mimicked hypoxia and adipokines. Here, OCCM-30 were co-stimulated with resistin, visfatin or ghrelin under CoCl2-mimicked hypoxia. In-vitro investigations revealed that CoCl2-induced hypoxia triggered activation of caspases, resulting in apoptosis dysfunction in cementoblasts. Resistin, visfatin and ghrelin promoted the phosphorylated ERK1/2 expression in OCCM-30 cells. Furthermore, these adipokines inhibited hypoxia-induced apoptosis at different degrees. These effects were reversed by pre-treatment with ERK inhibitor (FR180204). In cells treated with FR180204, HIF-1α expression was inhibited despite the presence of three adipokines. Using dominant-negative mutants of HIF-1α, we found that siHIF-1α negatively regulated the caspase-8, caspase-9 and caspase-3 gene expression. We concluded that HIF-1α acts as a bridge factor in lengthy hypoxia-induced apoptosis in an ERK1/2-dependent pathway. Gene expressions of the caspases-3, caspase-8 and caspase-9 were shown to be differentially regulated by adipokines (resistin, visfatin and ghrelin). Our study, therefore, provides evidence for the role of ERK1/2 and HIF-1α in the apoptotic response of OCCM-30 cells exposed to CoCl2-mimicked hypoxia, providing potential new possibilities for molecular intervention in obese patients undergoing orthodontic treatment. |