Hypoxia and Reoxygenation Augment Bone‐Resorbing Factor Production From Human Periodontal Ligament Cells

Motohira, Hitoshi; Hayashi, Joichiro; Tatsumi, Junichi; Tajima, Masamichi; Sakagami, Hiroshi; Shin, Kitetsu

doi:10.1902/jop.2007.060519

Cited by 52 publications

(52 citation statements)

References 38 publications

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“…Consistent with our findings, PGJ 2 has been shown to inhibit IL‐10‐induced p‐STAT3 in macrophages and THP‐1 cells [Ji et al, ]. Members of the mitogen‐activated protein kinase (MAPK) pathway have been implicated in increasing the activity of HIF in response to various stimuli [Motohira et al, ; Majmundar et al, 2010]. NF‐κB signal is an upstream mechanism that regulates HIF‐2α, since IL‐1β and TNF‐α, putative ligands of the NF‐κB signal, increase HIF‐2α expression in fibroblasts [Jung et al, ] and chondrocytes [Yang et al, ].…”

Section: Discussionsupporting

confidence: 86%

“…Hypoxia and reoxygenation are known to stimulate the production of VEGF, IL‐6, IL‐1β, and PGE 2 in PDLCs [Motohira et al, ], which could result in the resorption of alveolar bone in periodontitis. Mammalian cells adapt to changes in O 2 availability primarily through hypoxia‐inducible factors (HIFs) whose activity is regulated by their subunits (HIF‐1α and HIF‐2α) [Majmundar et al, ].…”

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confidence: 99%

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HIF‐2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells

Bae

Shin

Kang

et al. 2015

J of Cellular Biochemistry

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Recent reports suggest that hypoxia inducible factor-2α (HIF-2α) is a key regulator of osteoarthritis cartilage destruction. However, the precise role of HIF-2α in the inflammatory response and osteoclast differentiation remains unclear. The purpose of this study was to investigate the effect of HIF-2α on inflammatory cytokines, extracellular matrix (ECM) destruction enzymes, and osteoclastic differentiation in nicotine and lipopolysaccharide (LPS)-stimulated human periodontal ligament cells (PDLCs). HIF-2α was upregulated in chronically inflamed PDLCs of periodontitis patients, and in nicotine- and LPS-exposed PDLC in dose- and time-dependent manners. HIF-2α inhibitor and HIF-2α siRNA attenuated the nicotine- and LPS- induced production of NO and PGE2 , upregulation of iNOS, COX-2, pro-inflammatory cytokines (IL-1β, TNF-α, IL-1β, IL-6, IL-8, IL-10, IL-11, and IL-17), and matrix metalloproteinases (MMPs; MMP-1, -8, -13, -2 and -9), and reversed the effect on TIMPs (TIMP-1 and -2) in PDLCs. The conditioned medium produced by nicotine and LPS-treated PDLCs increased the number of TRAP-stained osteoclasts, TRAP activity and osteoclast-specific genes, which has been blocked by HIF-2α inhibition and silencing. HIF-2α inhibitor and HIF-2α siRNA inhibited the effects of nicotine and LPS on the activation of Akt, JAK2 and STAT3, ERK and JNK MAPK, nuclear factor-κB, c-Jun, and c-Fos. Taken together, this study is the first to demonstrate that HIF-2α inhibition exhibits anti-inflammatory activity through the inhibition of inflammatory cytokines and impairment of ECM destruction, as well as blocking of osteoclastic differentiation in a nicotine- and periodontopathogen-stimulated PDLCs model. Thus, HIF-2α inhibition may be a novel molecular target for therapeutic approaches in periodontitis.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

HIF‐2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells

Bae

Shin

Kang

et al. 2015

J of Cellular Biochemistry

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“…A previous report demonstrated that hypoxia stimulates the PDLFs to produce VEGF, IL-1β, IL-6 and prostaglandin E 2 (Motohira et al, 2007). Consistent with this report, incubation of PDLFs under hypoxic conditions induced the expression of VEGF, IL-1β, IL-6 and IL-8 in the present study.…”

Section: Discussionsupporting

confidence: 93%

“…Hypoxic treatment increases the expression of pro-inflammatory cytokines Although the stimulatory effects of mechanical compression on the expression of pro-inflammatory cytokines have been well known, there are only a few reports demonstrating the effect of hypoxia on the expression of pro-inflammatory cytokines in human PDLFs (Motohira et al, 2007). Therefore, we examined whether hypoxic treatment induces the expression of proinflammatory cytokines in PDLFs.…”

Section: Resultsmentioning

confidence: 96%

The Effect of Antioxidants on the Production of Pro-Inflammatory Cytokines and Orthodontic Tooth Movement

Chae

Park

Hwang

et al. 2011

Molecules and Cells

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Orthodontic force causes gradual compression of the periodontal ligament tissues, which leads to local hypoxia in the compression side of the tissues. In this study, we investigated whether antioxidants exert a regulatory effect on two factors: the expression of pro-inflammatory cytokines in human periodontal ligament fibroblasts (PDLFs) that were exposed to mechanical compression and hypoxia and the rate of orthodontic tooth movement in rats. Exposure of PDLFs to mechanical compression (0.5-3.0 g/cm 2 ) or hypoxic conditions increased the production of intracellular reactive oxygen species. Hypoxic treatment for 24 h increased the mRNA levels of IL-1β, IL-6 and IL-8 as well as vascular endothelial growth factor (VEGF) in PDLFs. Resveratrol (10 nM) or N-acetylcysteine (NAC, 20 mM) diminished the transcriptional activity of hypoxiainducible factor-1 and hypoxia-induced expression of VEGF. Combined treatment with mechanical compression and hypoxia significantly increased the expression levels of IL-1β, IL-6, IL-8, TNF-α and VEGF in PDLFs. These levels were suppressed by NAC and resveratrol. The maxillary first molars of rats were moved mesially for seven days using an orthodontic appliance. NAC decreased the amount of orthodontic tooth movement compared to the vehicletreated group. The results from immunohistochemical staining demonstrated that NAC suppressed the expression of IL-1β and TNF-α in the periodontal ligament tissues compared to the vehicle-treated group. These results suggest that antioxidants have the potential to negatively regulate the rate of orthodontic tooth movement through the down-regulation of pro-inflammatory cytokines in the compression sides of periodontal ligament tissues.

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“…VEGF is the primary mediator of angiogenesis, and it serves various biological functions, such as promoting chemotaxis (Clauss et al, 1996) and stimulating osteoclastogenesis (Knowles and Athanasou, 2008). Because previous studies have shown that hypoxia is a strong inducer of VEGF expression in PDLFs (Motohira et al, 2007), we examined VEGF mRNA levels in hypoxic conditions. Hypoxia increased VEGF mRNA expression, confirming that the GasPak pouch system provided effective hypoxic conditions (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Park

Baek

Lee

et al. 2011

Molecules and Cells

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During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the compression side of periodontal tissues. The receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/ stromal cell-derived factor that is essential for osteoclastogenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1α (HIF-1α) protein in PDLFs. Constitutively active HIF-1α alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL expression. To investigate further whether HIF-1α directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1α significantly increased RANKL promoter activity, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF-1α binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1α increased the DNA binding of HIF-1α to RANKL promoter. These results suggest that HIF-1α mediates hypoxia-induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs.

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Hypoxia and Reoxygenation Augment Bone‐Resorbing Factor Production From Human Periodontal Ligament Cells

Abstract: Hypoxia and reoxygenation may stimulate the PDL to produce VEGF, IL-6 and -1beta, and PGE2, which could result in the resorption of alveolar bone in periodontitis.

Cited by 52 publications

References 38 publications

HIF‐2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells

HIF‐2 Inhibition Supresses Inflammatory Responses and Osteoclastic Differentiation in Human Periodontal Ligament Cells

The Effect of Antioxidants on the Production of Pro-Inflammatory Cytokines and Orthodontic Tooth Movement

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

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