Transcriptomes in Healthy and Diseased Gingival Tissues

Demmer, Ryan T.; Behle, Jan H.; Wolf, Dana L.; Handfield, Martin; Kebschull, Moritz; Celenti, Romanita; Pavlidis, Paul; Papapanou, Panos N.

doi:10.1902/jop.2008.080139

Cited by 163 publications

(186 citation statements)

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“…First, we evaluated the expression of NK cell-related genes in human periodontitis lesions (n ϭ 241, from 120 patients each contributing Ն2 diseased tissue samples, with a mean probing pocket depth [PPD] of 6.58 Ϯ 1.91 mm; range, 4 to 11 mm) compared to clinically healthy gingivae (n ϭ 69, each patient contributing a healthy tissue sample, when available; PPD, 2.29 Ϯ 0.52 mm; range, 1 to 4 mm) (18,19). As summarized in Table 1, the predominant NK cell-activating gene with increased expression in periodontitis lesions versus health was the CRACC gene (3.18-fold; false discovery rate [FDR] ϭ 5.24 ϫ 10 Ϫ30 ); high correlation of array data and quantitiative PCR (qPCR) findings for this gene (Spearman's r ϭ Ϫ0.81; P ϭ 0.005) was shown previously (26).…”

Section: Resultsmentioning

confidence: 99%

“…Whole-genome gene expression profiles were generated using Affymetrix HG-U133plus 2.0 gene arrays from 310 gingival tissue samples (69 clinically healthy and 241 diseased) from 120 nonsmoking patients (55 with aggressive and 65 with chronic periodontitis) phenotyped with respect to demographic information, clinical periodontal status, and levels of subgingival bacteria with respect to 11 species, as described previously (18,19) (Columbia University Medical Center IRB approval number AAAB0896; GEO [Gene Expression Omnibus at the NCBI] accession number GSE16134). Data were analyzed using R/Bioconductor (limma and SPIA packages) and SAS (for population-specific expression analysis [PSEA] [20]).…”

Section: Methodsmentioning

confidence: 99%

“…These statistical models contain both fixed and random effects. Specifically, patients were conditioned as random effect in these models to account for the within-patient correlation in gene expression, as previously described (18).…”

Section: Methodsmentioning

confidence: 99%

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Role of the NK Cell-Activating Receptor CRACC in Periodontitis

et al. 2013

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Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cellactivating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Role of the NK Cell-Activating Receptor CRACC in Periodontitis

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“…We have earlier presented gingival tissue transcriptomic data from the same patients (Demmer et al, 2008;Papapanou et al, 2009), and demonstrated substantial differential gene expression between states of periodontal health and disease. Here, we extend this work and analyze differential expression of miRNAs in the same samples.…”

Section: Discussionmentioning

confidence: 99%

MicroRNAs and Their Target Genes in Gingival Tissues

et al. 2012

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A supplemental appendix to this article is published electronically only at http://jdr.sagepub.com/supplemental. AbstrActTo gain insights into the in vivo function of miRNAs in the context of periodontitis, we examined the occurrence of miRNAs in healthy and diseased gingival tissues and validated their in silico-predicted targets through mRNA profiling using whole-genome microarrays in the same specimens. Eighty-six individuals with periodontitis contributed 198 gingival papillae: 158 'diseased' (bleeding-on-probing, PD > 4 mm, and AL ≥ 3 mm) and 40 'healthy' (no bleeding, PD ≤ 4 mm, and AL ≤ 2 mm). Expression of 1,205 miRNAs was assessed by microarrays, followed by selected confirmation by quantitative RT-PCR. Predicted miRNA targets were identified and tested for enrichment by Gene Set Enrichment Analysis (GSEA). Enriched gene sets were grouped in functional categories by DAVID and Ingenuity Pathway Analysis. One hundred fifty-nine miRNAs were significantly differentially expressed between healthy and diseased gingiva. Four miRNAs (hsa-miR-451, hsa-miR-223, hsamiR-486-5p, hsa-miR-3917) were significantly overexpressed, and 7 (hsa-miR-1246, hsa-miR-1260, hsa-miR-141, hsa-miR-1260b, hsa-miR-203, hsa-miR-210, hsa-miR-205*) were underexpressed by > 2-fold in diseased vs. healthy gingiva. GSEA and additional filtering identified 60 enriched miRNA gene sets with target genes involved in immune/inflammatory responses and tissue homeostasis. This is the first study that concurrently examined miRNA and mRNA expression in gingival tissues and will inform mechanistic experimentation to dissect the role of miRNAs in periodontal tissue homeostasis and pathology.

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“…We used 310 Affymetrix HG-U133Plus2.0 microarray samples (GEO accession number GSE16134) of 'healthy' [n = 69, no bleeding on probing (BoP), probing depth (PD) ≤ 4 mm, and clinical attachment loss (CAL) ≤ 4 mm)] or 'diseased' gingival tissue samples (n = 241; with BoP, PD ≥ 4 mm, and CAL ≥ 3 mm), obtained from 120 non-smoking, systemically healthy individuals with moderate/severe periodontitis (65 with CP and 55 with AgP), as previously described (Demmer et al, 2008;Kebschull and Papapanou, 2010). Excellent correlation of array data and confirmatory qPCR was shown previously (Papapanou et al, 2009).…”

Section: Methodsmentioning

confidence: 99%

Molecular Differences between Chronic and Aggressive Periodontitis

et al. 2013

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The 2 major forms of periodontitis, chronic (CP) and aggressive (AgP), do not display sufficiently distinct histopathological characteristics or microbiological/ immunological features. We used molecular profiling to explore biological differences between CP and AgP and subsequently carried out supervised classification using machine-learning algorithms including an internal validation. We used whole-genome gene expression profiles from 310 'healthy' or 'diseased' gingival tissue biopsies from 120 systemically healthy non-smokers, 65 with CP and 55 with AgP, each contributing with ≥ 2 'diseased' gingival papillae (n = 241; with bleeding-on-probing, probing depth ≥ 4 mm, and clinical attachment loss ≥ 3 mm), and, when available, a 'healthy' papilla (n = 69; no bleeding-on-probing, probing depth ≤ 4 mm, and clinical attachment loss ≤ 4 mm). Our analyses revealed limited differences between the gingival tissue transcriptional profiles of AgP and CP, with genes related to immune responses, apoptosis, and signal transduction overexpressed in AgP, and genes related to epithelial integrity and metabolism overexpressed in CP. Different classifying algorithms discriminated CP from AgP with an area under the curve ranging from 0.63 to 0.99. The small differences in gene expression and the highly variable classifier performance suggest limited dissimilarities between established AgP and CP lesions. Future analyses may facilitate the development of a novel, 'intrinsic' classification of periodontitis based on molecular profiling.

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Transcriptomes in Healthy and Diseased Gingival Tissues

Abstract: Gingival tissue transcriptomes provide a valuable scientific tool for further hypothesis-driven studies of the pathobiology of periodontitis.

Cited by 163 publications

References 34 publications

Role of the NK Cell-Activating Receptor CRACC in Periodontitis

Role of the NK Cell-Activating Receptor CRACC in Periodontitis

MicroRNAs and Their Target Genes in Gingival Tissues

Molecular Differences between Chronic and Aggressive Periodontitis

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