Aggressive periodontitis and NOD2 variants

Mizuno, Noriyoshi; Kume, Kodai; Nagatani, Yukiko; Matsuda, Shinji; Iwata, Takeo; Ouhara, Kazuhisa; Kajiya, Mikihito; Takeda, Katsuhiro; Matsuda, Yukiko; Tada, Yui; Ohsawa, Ryosuke; Morino, Hiroyuki; Mihara, Keichiro; Fujita, Tsuyoshi; Kawaguchi, Hiroyuki; Shiba, Hideki; Kawakami, Hideshi; Kurihara, Hidemi

doi:10.1038/s10038-020-0777-z

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…(75,76) In humans and mice, NOD1/2 signaling pathways are known to regulate periodontitis and periodontitis-related bone loss. (30,(77)(78)(79)(80)(81)(82)(83)(84) Specifically, in mouse LIP, activation of the NOD1 pathway, but not NOD2, has been shown to be responsible for alveolar bone resorption. (30) In contrast, the roles of TLR2 and TLR4, cell membrane receptors that recognize bacterial lipopeptides and LPS, respectively, (85) in LIP remain elusive.…”

Section: Discussionmentioning

confidence: 99%

Osteocyte RANKL Drives Bone Resorption in Mouse Ligature-Induced Periodontitis

Kittaka,

Yoshimoto,

Levitan

et al. 2023

Journal of Bone and Mineral Research

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Mouse ligature‐induced periodontitis (LIP) has been used to study bone loss in periodontitis. However, the role of osteocytes in LIP remains unclear. Furthermore, there is no consensus on the choice of alveolar bone parameters and time points to evaluate LIP. Here, we investigated the dynamics of changes in osteoclastogenesis and bone volume (BV) loss in LIP over 14 days. Time course analysis revealed that osteoclast induction peaked on days 3 and 5, followed by the peak of BV loss on day 7. Notably, BV was restored by day 14. The bone formation phase following the bone resorption phase was suggested to be responsible for the recovery of bone loss. Electron microscopy identified bacteria in the osteocyte lacunar space beyond the periodontal ligament (PDL) tissue. We investigated how osteocytes affect bone resorption of LIP and found that mice lacking receptor activator of NF‐κB ligand (RANKL), predominantly in osteocytes, protected against bone loss in LIP, whereas recombination activating 1 (RAG1)‐deficient mice failed to resist it. These results indicate that T/B cells are dispensable for osteoclast induction in LIP and that RANKL from osteocytes and mature osteoblasts regulates bone resorption by LIP. Remarkably, mice lacking the myeloid differentiation primary response gene 88 (MYD88) did not show protection against LIP‐induced bone loss. Instead, osteocytic cells expressed nucleotide‐binding oligomerization domain containing 1 (NOD1), and primary osteocytes induced significantly higher Rankl than primary osteoblasts when stimulated with a NOD1 agonist. Taken together, LIP induced both bone resorption and bone formation in a stage‐dependent manner, suggesting that the selection of time points is critical for quantifying bone loss in mouse LIP. Pathogenetically, the current study suggests that bacterial activation of osteocytes via NOD1 is involved in the mechanism of osteoclastogenesis in LIP. The NOD1‐RANKL axis in osteocytes may be a therapeutic target for bone resorption in periodontitis.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Osteocyte RANKL Drives Bone Resorption in Mouse Ligature-Induced Periodontitis

Kittaka,

Yoshimoto,

Levitan

et al. 2023

Journal of Bone and Mineral Research

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“…GWAS analysis of AP patients in a Japanese population identified putative polymorphism in the GPR126 gene locus, and in vitro analysis implied that this polymorphism influenced the functions of GPR126 for osteogenic differentiation of PDL cells [22] , [23] . Furthermore, 2 studies conducting whole exome sequencing of AP families and sporadic patients from different groups identified 8 mutation points in NOD2 [24] , [25] . Among these, p.Arg311Trp mutations were commonly identified in both studies [24] , [25] .…”

Section: Genetic Factors Of Periodontitismentioning

confidence: 99%

“…Furthermore, 2 studies conducting whole exome sequencing of AP families and sporadic patients from different groups identified 8 mutation points in NOD2 [24] , [25] . Among these, p.Arg311Trp mutations were commonly identified in both studies [24] , [25] . NOD2 is an intracellular sensor of bacterial peptidoglycan and participates in innate immunity.…”

Section: Genetic Factors Of Periodontitismentioning

confidence: 99%

Epigenetics in susceptibility, progression, and diagnosis of periodontitis

Suzuki

Yamada

2022

Japanese Dental Science Review

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“…The genetic backdrop of all forms of early-onset periodontitis is based on inborn neutrophil defects ( 18 , 63 ) or on other inborn genetic defects leading to neutrophil activation ( 64 ). The concomitant dysbiosis in early-onset periodontitis is hence a consequence of inborn immune deficiency.…”

Section: Immunity Dysregulation As Instigator Of Periodontitismentioning

confidence: 99%

“…Carriership of the NOD2 genetic risk for Crohn’s disease is associated with an increased relative abundance of Enterobacteriaceae ( 77 ). An increased risk of periodontitis among patients with Crohn’s disease has been well established ( 63 , 78 ).…”

Section: Immunity Dysregulation As Instigator Of Periodontitismentioning

confidence: 99%

Neutrophils Orchestrate the Periodontal Pocket

et al. 2021

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The subgingival biofilm attached to tooth surfaces triggers and maintains periodontitis. Previously, late-onset periodontitis has been considered a consequence of dysbiosis and a resultant polymicrobial disruption of host homeostasis. However, a multitude of studies did not show “healthy” oral microbiota pattern, but a high diversity depending on culture, diets, regional differences, age, social state etc. These findings relativise the aetiological role of the dysbiosis in periodontitis. Furthermore, many late-onset periodontitis traits cannot be explained by dysbiosis; e.g. age-relatedness, attenuation by anti-ageing therapy, neutrophil hyper-responsiveness, and microbiota shifting by dysregulated immunity, yet point to the crucial role of dysregulated immunity and neutrophils in particular. Furthermore, patients with neutropenia and neutrophil defects inevitably develop early-onset periodontitis. Intra-gingivally injecting lipopolysaccharide (LPS) alone causes an exaggerated neutrophil response sufficient to precipitate experimental periodontitis. Vice versa to the surplus of LPS, the increased neutrophil responsiveness characteristic for late-onset periodontitis can effectuate gingiva damage likewise. The exaggerated neutrophil extracellular trap (NET) response in late-onset periodontitis is blameable for damage of gingival barrier, its penetration by bacteria and pathogen-associated molecular patterns (PAMPs) as well as stimulation of Th17 cells, resulting in further neutrophil activation. This identifies the dysregulated immunity as the main contributor to periodontal disease.

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Aggressive periodontitis and NOD2 variants

Cited by 8 publications

References 21 publications

Osteocyte RANKL Drives Bone Resorption in Mouse Ligature-Induced Periodontitis

Osteocyte RANKL Drives Bone Resorption in Mouse Ligature-Induced Periodontitis

Epigenetics in susceptibility, progression, and diagnosis of periodontitis

Neutrophils Orchestrate the Periodontal Pocket

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