Hypoxia‐inducible factor 1‐alpha acts as a bridge factor for crosstalk between ERK1/2 and caspases in hypoxia‐induced apoptosis of cementoblasts

Yong, Jiawen; Bremen, Julia von; Groeger, Sabine; Ruiz‐Heiland, Gisela; Ruf, Sabine

doi:10.1111/jcmm.16920

Cited by 13 publications

(19 citation statements)

References 41 publications

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“…Our present data revealed that compressive force at the magnitude of 2.4 gf/cm 2 triggered the HIF-1α expression. However, the mRNA levels decreased rapidly from 12 h stimulation possibly due to the initiation of apoptotic processes [2]. In this study, we clarified the expression of P. gingivalis PGN-induced PD-L1 and correlation of PD-L1/HIF-1α in cementoblasts.…”

Section: Discussionmentioning

confidence: 80%

“…Compression is one hallmark of the specific microenvironments induced by orthodontic compressive force (CF) during orthodontic tooth movement (OTM), due to its capability to affect the cementoblasts homeostasis [1]. During OTM, compressive force triggers inflammatory osteoclastogenic and remodeling processes in the periodontal ligament (PDL) to further create an immune suppressive hypoxic microenvironment, which impairs the process of OTM [2]. The role of compressive force on the physiology of cementum has received increasing interest because orthodontically induced inflammatory root resorption (OIIRR) is a serious side effect of orthodontic tooth movement [3].…”

Section: Introductionmentioning

confidence: 99%

“…The hypoxia-inducible PD-L1 expression has been revealed in multiple primary and various carcinoma cell types [15,16]. The hypoxia-induced transcription factors (HIF) are crucial regulators of the transcriptional responses to orthodontic forces [17] and have been reported to regulate the apoptosis process of cementoblasts [2]. However, it is currently largely unknown whether HIF-1α regulates PD-L1 expression in cementoblasts.…”

Section: Introductionmentioning

confidence: 99%

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Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

Yong

Gröger

Meyle

et al. 2022

IJMS

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Patients with periodontitis undergoing orthodontic therapy may suffer from undesired dental root resorption. The purpose of this in vitro study was to investigate the molecular mechanisms resulting in PD-L1 expression of cementoblasts in response to infection with Porphyromonas gingivalis (P. gingivalis) peptidoglycan (PGN) and compressive force (CF), and its interaction with hypoxia-inducible factor (HIF)-1α molecule.: The cementoblast (OCCM-30) cells were kinetically infected with various concentrations of P. gingivalis PGN in the presence and absence of CF. Western blotting and RT-qPCR were performed to examine the protein expression of PD-L1 and HIF-1α as well as their gene expression. Immunofluorescence was applied to visualize the localization of these proteins within cells. An HIF-1α inhibitor was added for further investigation of necroptosis by flow cytometry analysis. Releases of soluble GAS-6 were measured by ELISA. P. gingivalis PGN dose dependently stimulated PD-L1 upregulation in cementoblasts at protein and mRNA levels. CF combined with P. gingivalis PGN had synergistic effects on the induction of PD-L1. Blockade of HIF-1α inhibited the P. gingivalis PGN-inducible PD-L1 protein expression under compression, indicating an HIF-1α dependent regulation of PD-L1 induction. Concomitantly, an HIF-1α inhibitor decreased the GAS-6 release in the presence of CF and P. gingivalis PGN co-stimulation. The data suggest that PGN of P. gingivalis participates in PD-L1 up-regulation in cementoblasts. Additionally, the influence of compressive force on P. gingivalis PGN-induced PD-L1 expression occurs in HIF-1α dependently. In this regard, HIF-1α may play roles in the immune response of cementoblasts via immune-inhibitory PD-L1. Our results underline the importance of molecular mechanisms involved in bacteria-induced periodontics and root resorption.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

Yong

Gröger

Meyle

et al. 2022

IJMS

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“…Together from previous studies [ 12 – 15 ], the ribosomal 60S protein L22 ( RPL22 ), Peptidylprolyl isomerase B ( PPIB ), polymerase RNA II polypeptide A ( POLR2A ), Ribosomal protein, large, P0 ( RPLP0 ), glucuronidase, beta ( GUSB ), Actin-beta ( β-actin ), TATA-binding protein ( TBP ), ubiquitin C ( UBC ), glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ), Tyrosine 3-monooxygenase/tryptophan 5-mono-oxygenase activate protein, zeta ( YWHAZ ), eukaryotic translation elongation factor 1 alpha 1 ( EEF1A1 ), Ribosomal protein L18 ( RPL ) and beta-5 class I ( TUBB ) were identified as reliable reference genes.…”

Section: Introductionmentioning

confidence: 88%

Selection and validation of reference gene for RT-qPCR studies in co-culture system of mouse cementoblasts and periodontal ligament cells

et al. 2022

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Objective RT-qPCR is a reliable method for gene expression analysis, but the accuracy of the quantitative data depends on the appropriate selection of reference genes. A Co-culture system consisting of periodontal ligament cells (SV-PDL) and cementoblasts (OCCM-30) to investigate the crosstalk between these two cell lines under orthodontic condition is essential for experimental orthodontic setups in-vitro. Therefore, we aimed to identify a set of reliable reference genes suitable for RT-qPCR studies for prospective co-culture systems of OCCM-30 and SV-PDL cells. Results The results demonstrated that PPIB, GUSB and RPLP0 turned out to be the three most stable reference genes for OCCM-30 in the co-culture system, while PPIB, POLR2A and RPLP0 have the three highest rankings for SV-PDL cells in the co-culture system. The most stable gene combination were PPIB and POLR2A in the co-culture system. In conclusion, PPIB is overall the most stably expressed reference gene for OCCM-30 or SV-PDL cell line in the system. The combination of PPIB and POLR2A as reference genes are indicated to be the potential and mandatory to obtain accurate quantification results for normalizing RT-qPCR data in genes of interest expression in these two cell lines co-culture systems.

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“…Cementoblasts, highly differentiated periodontal ligament (PDL) cells, are located on the cementum [ 13 ]. The apoptotic death of cementoblasts might contribute to orthodontically induced inflammatory root resorptions (OIIRR) during orthodontic tooth movement (OTM) [ 14 ]. One of the most distinctly activated apoptotic signals was the caspase (cysteinyl aspartate proteinases) family, which executes the extrinsic and intrinsic apoptosis pathways [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Ciliary Neurotrophic Factor (CNTF) and Its Receptors Signal Regulate Cementoblasts Apoptosis through a Mechanism of ERK1/2 and Caspases Signaling

Yong

Groeger

Bremen

et al. 2022

IJMS

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Ciliary neurotrophic factor (CNTF) was identified as a survival factor in various types of peripheral and central neurons, glia and non-neural cells. At present, there is no available data on the expression and localization of CNTF-receptors in cementoblasts as well as on the role of exogenous CNTF on this cell line. The purpose of this study was to determine if cementoblasts express CNTF-receptors and analyze the mechanism of its apoptotic regulation effects on cementoblasts. OCCM-30 cementoblasts were cultivated and stimulated kinetically using CNTF protein (NBP2-35168, Novus Biologicals). Quantified transcriptional (RT-qPCR) and translational (WB) products of CNTFRα, IL-6Rα (CD126), LIFR, p-GP130, GP130, p-ERK1/2, ERK1/2, Caspase-8, -9, -3 and cleaved-caspase-3 were evaluated. Immunofluorescence (IF) staining was applied to visualize the localization of the CNTF-receptors within cells. The apoptosis ratio was measured with an Annexin-V FITC/PI kit. The ERK1/2 antagonist (FR180204, Calbiochem) was added for further investigation by flow cytometry analysis. The CNTF-receptor complex (CNTFRα, LIFR, GP130) was functionally up-regulated in cementoblasts while cultivated with exogenous CNTF. CNTF significantly attenuated cell viability and proliferation for long-term stimulation. Flow cytometry analysis shows that CNTF enhanced the apoptosis after prolonged duration. However, after only a short-term period, CNTF halts the apoptosis of cementoblasts. Further studies revealed that CNTF activated phosphorylated GP130 and the anti-apoptotic molecule ERK1/2 signaling to participate in the regulation of the apoptosis ratio of cementoblasts. In conclusion, CNTF elicited the cellular functions through a notable induction of its receptor complex in cementoblasts. CNTF has an inhibitory effect on the cementoblast homeostasis. These data also elucidate a cellular mechanism for an exogenous CNTF-triggered apoptosis regulation in a mechanism of ERK1/2 and caspase signaling and provides insight into the complex cellular responses induced by CNTF in cementoblasts.

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Hypoxia‐inducible factor 1‐alpha acts as a bridge factor for crosstalk between ERK1/2 and caspases in hypoxia‐induced apoptosis of cementoblasts

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 13 publications

References 41 publications

Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

Selection and validation of reference gene for RT-qPCR studies in co-culture system of mouse cementoblasts and periodontal ligament cells

Ciliary Neurotrophic Factor (CNTF) and Its Receptors Signal Regulate Cementoblasts Apoptosis through a Mechanism of ERK1/2 and Caspases Signaling

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