NOD2 Mediates Odontoblast Differentiation and RANKL Expression

Lee, S.-I.; Kim, G.-T.; Kim, H.J.; Park, S.-H.; Kim, E.-C.

doi:10.1177/0022034514535214

Cited by 26 publications

(19 citation statements)

References 26 publications

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“…TRAP‐positive multinucleated cells containing three or more nuclei were counted as osteoclasts under a light microscope. To access the osteoclastogenic activity of CM from HPDLCs, pre‐osteoclasts (BMMs treated for 2 days with M‐CSF and RANKL) were further cultured up to 4 days in the presence of CM obtained from HPDLCs with PGJ 2 or HIF‐2α siRNA as previously described [Lee et al, ].…”

Section: Methodsmentioning

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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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: Methodsmentioning

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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“…These modules drive the production of proinflammatory cytokines/chemokines such as interleukin- (IL-) 1, tumor necrosis factor- (TNF-) α , and IL-6 [ 1 , 2 , 5 ]. Cytokines are multifunctional proteins that regulate osteoclast formation and hence bone resorption, modify vascular endothelial permeability, and recruit immune cells to inflamed tissue [ 2 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp

Shin

Lee

et al. 2015

Mediators of Inflammation

114

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Pathogen recognition receptors (PRRs) are a class of germ line-encoded receptors that recognize pathogen-associated molecular patterns (PAMPs). The activation of PRRs is crucial for the initiation of innate immunity, which plays a key role in first-line defense until more specific adaptive immunity is developed. PRRs differ in the signaling cascades and host responses activated by their engagement and in their tissue distribution. Currently identified PRR families are the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), the nucleotide-binding oligomerization domain-like receptors (NLRs), the retinoic acid-inducible gene-I-like receptors (RLRs), and the AIM2-like receptor (ALR). The environment of the dental pulp is substantially different from that of other tissues of the body. Dental pulp resides in a low compliance root canal system that limits the expansion of pulpal tissues during inflammatory processes. An understanding of the PRRs in dental pulp is important for immunomodulation and hence for developing therapeutic targets in the field of endodontics. Here we comprehensively review recent finding on the PRRs and the mechanisms by which innate immunity is activated. We focus on the PRRs expressed on dental pulp and periapical tissues and their role in dental pulp inflammation.

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“…However, it has been shown that the activation of NOD2, by bacterial stimulation, displays an alternative role, leading to a suppressed production of inflammatory mediators, but this function is not fully determined (Chauhan and Marriott, 2010). Lee et al (2014) observed that human dental pulp cells stimulated by MDP increase the expression of cytokines (TNF-α, IL-1β, IL-6, IL-11, IL-17) that positively regulate osteoclasts differentiation. They also observed that MDP promoted increased RANKL and M-CSF and reduced OPG expression by dental pulp cells.…”

mentioning

confidence: 99%

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

et al. 2014

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The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2-/- mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2-/- infected mice. Moreover, the expression of 2 osteoclast activity markers—cathepsin K and matrix metalloproteinase 9—was significantly lower in gingival tissue from NOD2-/- infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity.

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NOD2 Mediates Odontoblast Differentiation and RANKL Expression

Cited by 26 publications

References 26 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

An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

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