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MicroRNAs in Periodontal Disease and Systemic Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 8580

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Prof. Dr. Lakshmyya Kesavalu

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Guest Editor

Department of Periodontology, College of Dentistry, University of Florida, Gainesville, FL 32610, USA
Interests: miRNAs in periodontal disease and systemic diseases; miRNA in experimental periodontitis; miRNA in periodontal disease therapeutics; miRNAs in experimental periodontitis and atherosclerosis; association of periodontal pathogens, miRNAs, and Alzheimer’s disease; the link between periodontal pathogens, miRNA and Sjogren’s syndrome

Prof. Dr. Edward K. L. Chan

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Guest Editor

Department of Oral Biology, University of Florida, Gainesville, FL 32610, USA
Interests: miRNA in endotoxin tolerance; miRNA in systemic autoimmune diseases; miRNA in oral cancer; molecular and cell biology of miRNA

Special Issue Information

Dear Colleagues,

Periodontitis is a chronic inflammatory polymicrobial dysbiotic disease that affects the periodontal tissues such as gingiva, periodontal ligament and alveolar bone. Recent evidence shown that periodontitis is closely associated with various systemic diseases like cardiovascular diseases, Alzheimer’s Disease, rheumatoid arthritis, Diabetes mellitus, and preterm birth and low birth weight. microRNA (miRNA) are small non-coding regulatory RNAs that play a major role in immune inflammatory mediated periodontal disease and participate in the regulation of gene expression interfering with multiple genetic targets. Many in vivo and published pre-clinical studies showed that miRNAs are overexpressed in diseased gingival tissues, gingival crevicular fluid (GCF), saliva, serum and are excellent candidate biomarkers in chronic periodontitis, apical peridontitis and peri-implantitis. As miRNA affects both innate and adaptive immune systems, studying miRNA in inflammatory mediated periodontal disease will aid in developing prognostic/diagnostic biomarkers for both periodontitis and other systemic diseases. Considering the importance of studying the biological functions of miRNAs in periodontal disease and other sytemic diseases, this special issue on miRNAs in periodontal disease and systemic diseases will highlight recent advances in this field of research. This special issue is dedicated to researh articles and reviews regarding miRNA profiling associated with periodontal disease, identifcation of potential prognostic/diagnostic biomarkers for periodontal diseases and other systemic diseases, differential miRNA expression in periodontal disease using animal models, and identification of miRNAs that potentially link periodontitis and other systemic diseases. This Special Issue also welcomes Original Research articles, Reviews, and Mini reviews that provide latest key findings in miRNA biology.

Prof. Dr. Lakshmyya Kesavalu
Prof. Dr. Edward K. L. Chan
Guest Editors

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Keywords

miRNAs and periodontal disease and peri-implantitis
miRNAs molecular mechanism in periodontal ligament cells
bacteria and virus-induced miRNAs in Periodontal disease
experimenatl periodontitis, animal model, and miRNA
miRNAs in periodontitis with diabetes mellitus
miRNAs as biomarkers (serum, saliva, GCF) in periodontitis and cardiovascular diseases

Published Papers (5 papers)

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Research

25 pages, 3911 KiB

Open AccessArticle

Unique miRomics Expression Profiles in Tannerella forsythia-Infected Mandibles during Periodontitis Using Machine Learning

by Chairmandurai Aravindraja, Syam Jeepipalli, William Duncan, Krishna Mukesh Vekariya, Sakshee Bahadekar, Edward K. L. Chan and Lakshmyya Kesavalu

Int. J. Mol. Sci. 2023, 24(22), 16393; https://doi.org/10.3390/ijms242216393 - 16 Nov 2023

Viewed by 1223

Abstract

T. forsythia is a subgingival periodontal bacterium constituting the subgingival pathogenic polymicrobial milieu during periodontitis (PD). miRNAs play a pivotal role in maintaining periodontal tissue homeostasis at the transcriptional, post-transcriptional, and epigenetic levels. The aim of this study was to characterize the global microRNAs (miRNA, miR) expression kinetics in 8- and 16-week-old T. forsythia-infected C57BL/6J mouse mandibles and to identify the miRNA bacterial biomarkers of disease process at specific time points. We examined the differential expression (DE) of miRNAs in mouse mandibles (n = 10) using high-throughput NanoString nCounter^® miRNA expression panels, which provided significant advantages over specific candidate miRNA or pathway analyses. All the T. forsythia-infected mice at two specific time points showed bacterial colonization (100%) in the gingival surface, along with a significant increase in alveolar bone resorption (ABR) (p < 0.0001). We performed a NanoString analysis of specific miRNA signatures, miRNA target pathways, and gene network analysis. A total of 115 miRNAs were DE in the mandible tissue during 8 and 16 weeks The T. forsythia infection, compared with sham infection, and the majority (99) of DE miRNAs were downregulated. nCounter miRNA expression kinetics identified 67 downregulated miRNAs (e.g., miR-375, miR-200c, miR-200b, miR-34b-5p, miR-141) during an 8-week infection, whereas 16 upregulated miRNAs (e.g., miR-1902, miR-let-7c, miR-146a) and 32 downregulated miRNAs (e.g., miR-2135, miR-720, miR-376c) were identified during a 16-week infection. Two miRNAs, miR-375 and miR-200c, were highly downregulated with >twofold change during an 8-week infection. Six miRNAs in the 8-week infection (miR-200b, miR-141, miR-205, miR-423-3p, miR-141-3p, miR-34a-5p) and two miRNAs in the 16-week infection (miR-27a-3p, miR-15a-5p) that were downregulated have also been reported in the gingival tissue and saliva of periodontitis patients. This preclinical in vivo study identified T. forsythia-specific miRNAs (miR-let-7c, miR-210, miR-146a, miR-423-5p, miR-24, miR-218, miR-26b, miR-23a-3p) and these miRs have also been reported in the gingival tissues and saliva of periodontitis patients. Further, several DE miRNAs that are significantly upregulated (e.g., miR-101b, miR-218, miR-127, miR-24) are also associated with many systemic diseases such as atherosclerosis, Alzheimer’s disease, rheumatoid arthritis, osteoarthritis, diabetes, obesity, and several cancers. In addition to DE analysis, we utilized the XGBoost (eXtreme Gradient boost) and Random Forest machine learning (ML) algorithms to assess the impact that the number of miRNA copies has on predicting whether a mouse is infected. XGBoost found that miR-339-5p was most predictive for mice infection at 16 weeks. miR-592-5p was most predictive for mice infection at 8 weeks and also when the 8-week and 16-week results were grouped together. Random Forest predicted miR-592 as most predictive at 8 weeks as well as the combined 8-week and 16-week results, but miR-423-5p was most predictive at 16 weeks. In conclusion, the expression levels of miR-375 and miR-200c family differed significantly during disease process, and these miRNAs establishes a link between T. forsythia and development of periodontitis genesis, offering new insights regarding the pathobiology of this bacterium. Full article

(This article belongs to the Special Issue MicroRNAs in Periodontal Disease and Systemic Diseases)

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19 pages, 2146 KiB

Open AccessArticle

Oral Spirochete Treponema denticola Intraoral Infection Reveals Unique miR-133a, miR-486, miR-126-3p, miR-126-5p miRNA Expression Kinetics during Periodontitis

by Chairmandurai Aravindraja, Syam Jeepipalli, Krishna Mukesh Vekariya, Ruben Botello-Escalante, Edward K. L. Chan and Lakshmyya Kesavalu

Int. J. Mol. Sci. 2023, 24(15), 12105; https://doi.org/10.3390/ijms241512105 - 28 Jul 2023

Cited by 1 | Viewed by 1702

Abstract

miRNAs are major regulators of eukaryotic gene expression and host immunity, and play an important role in the inflammation-mediated pathways in periodontal disease (PD) pathogenesis. Expanding our previous observation with the global miRNA profiling using partial human mouth microbes, and lack of in vivo studies involving oral spirochete Treponema denticola-induced miRNAs, this study was designed to delineate the global miRNA expression kinetics during progression of periodontitis in mice infected with T. denticola by using NanoString nCounter^® miRNA panels. All of the T. denticola-infected male and female mice at 8 and 16 weeks demonstrated bacterial colonization (100%) on the gingival surface, and an increase in alveolar bone resorption (p < 0.0001). A total of 70 miRNAs with at least 1.0-fold differential expression/regulation (DE) (26 upregulated and 44 downregulated) were identified. nCounter miRNA expression profiling identified 13 upregulated miRNAs (e.g., miR-133a, miR-378) and 25 downregulated miRNAs (e.g., miR-375, miR-34b-5p) in T. denticola-infected mouse mandibles during 8 weeks of infection, whereas 13 upregulated miRNAs (e.g., miR-486, miR-126-5p) and 19 downregulated miRNAs (miR-2135, miR-142-3p) were observed during 16 weeks of infection. One miRNA (miR-126-5p) showed significant difference between 8 and 16 weeks of infection. Interestingly, miR-126-5p has been presented as a potential biomarker in patients with periodontitis and coronary artery disease. Among the upregulated miRNAs, miR-486, miR-126-3p, miR-126-5p, miR-378a-3p, miR-22-3p, miR-151a-3p, miR-423-5p, and miR-221 were reported in human gingival plaques and saliva samples from periodontitis and with diabetes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed various functional pathways of DE miRNAs, such as bacterial invasion of epithelial cells, Ras signaling, Fc gamma R-mediated phagocytosis, osteoclast differentiation, adherens signaling, and ubiquitin mediated proteolysis. This is the first study of DE miRNAs in mouse mandibles at different time-points of T. denticola infection; the combination of three specific miRNAs, miR-486, miR-126-3p, and miR-126-5p, may serve as an invasive biomarker of T. denticola in PD. These miRNAs may have a significant role in PD pathogenesis, and this research establishes a link between miRNA, periodontitis, and systemic diseases. Full article

(This article belongs to the Special Issue MicroRNAs in Periodontal Disease and Systemic Diseases)

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18 pages, 5879 KiB

Open AccessArticle

Gingival Tissue MiRNA Expression Profiling and an Analysis of Periodontitis-Specific Circulating MiRNAs

by Benita Buragaite-Staponkiene, Adomas Rovas, Alina Puriene, Kristina Snipaitiene, Egle Punceviciene, Arunas Rimkevicius, Irena Butrimiene and Sonata Jarmalaite

Int. J. Mol. Sci. 2023, 24(15), 11983; https://doi.org/10.3390/ijms241511983 - 26 Jul 2023

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Abstract

This study aimed to identify the microRNAs (miRNAs) associated with periodontitis (PD) in gingival tissues, and to evaluate the levels of these selected miRNAs in the saliva and blood plasma among participants with and without rheumatoid arthritis (RA). A genome-wide miRNA expression analysis in 16 gingival tissue samples revealed 177 deregulated miRNAs. The validation of the miRNA profiling results in 80 gingival tissue samples revealed that the PD-affected tissues had a higher expression of miR-140-3p and -145-5p, while the levels of miR-125a-3p were significantly lower in inflamed tissues. After a thorough validation, four miRNAs, namely miR-140-3p, -145-5p, -146a-5p, and -195-5p, were selected for further analysis in a larger sample of salivary (N = 173) and blood plasma (N = 221) specimens. Increased salivary levels of miR-145-5p were associated with higher mean values of pocket probing depth and bleeding on probing index. The plasma-derived levels of miR-140-3p were higher among the participants with PD. In conclusion, the gingival levels of miR-140-3p, -145-5p, and -125a-3p were independently associated with PD presence and severity. The salivary and blood plasma levels of the target miRNAs were diversely related to PD. Similar miRNA associations with PD were observed among the participants with and without RA. Full article

(This article belongs to the Special Issue MicroRNAs in Periodontal Disease and Systemic Diseases)

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14 pages, 1525 KiB

Open AccessArticle

Specific microRNA Signature Kinetics in Porphyromonas gingivalis-Induced Periodontitis

by Chairmandurai Aravindraja, Krishna Mukesh Vekariya, Ruben Botello-Escalante, Shaik O. Rahaman, Edward K. L. Chan and Lakshmyya Kesavalu

Int. J. Mol. Sci. 2023, 24(3), 2327; https://doi.org/10.3390/ijms24032327 - 24 Jan 2023

Cited by 3 | Viewed by 1818

Abstract

Porphyromonas gingivalis is one of the major bacteria constituting the subgingival pathogenic polymicrobial milieu during periodontitis. Our objective is to determine the global microRNA (miRNA, miR) expression kinetics in 8- and 16-weeks duration of P. gingivalis infection in C57BL/6J mice and to identify the miRNA signatures at specific time-points in mice. We evaluated differential expression (DE) miRNAs in mandibles (n = 10) using high-throughput NanoString nCounter^® miRNA expression panels. The bacterial colonization, alveolar bone resorption (ABR), serum immunoglobulin G (IgG) antibodies, and bacterial dissemination were confirmed. In addition, all the infected mice showed bacterial colonization on the gingival surface, significant increases in ABR (p < 0.0001), and specific IgG antibody responses (p < 0.05–0.001). The miRNA profiling showed 26 upregulated miRNAs (e.g., miR-804, miR-690) and 14 downregulated miRNAs (e.g., miR-1902, miR-1937a) during an 8-weeks infection, whereas 7 upregulated miRNAs (e.g., miR-145, miR-195) and one downregulated miR-302b were identified during a 16-weeks infection. Both miR-103 and miR-30d were commonly upregulated at both time-points, and all the DE miRNAs were unique to the specific time-points. However, miR-31, miR-125b, miR-15a, and miR-195 observed in P. gingivalis-infected mouse mandibles were also identified in the gingival tissues of periodontitis patients. None of the previously identified miRNAs reported in in vitro studies using cell lines (periodontal ligament cells, gingival epithelial cells, human leukemia monocytic cell line (THP-1), and B cells) exposed to P. gingivalis lipopolysaccharide were observed in the in vivo study. Most of the pathways (endocytosis, bacterial invasion, and FcR-mediated phagocytosis) targeted by the DE miRNAs were linked with bacterial pathogen recognition and clearance. Further, eighteen miRNAs were closely associated with the bacterial invasion of epithelial cells. This study highlights the altered expression of miRNA in gingiva, and their expression depends on the time-points of infection. This is the first in vivo study that identified specific signature miRNAs (miR-103 and miR-30d) in P. gingivalis invasion of epithelial cells, establishes a link between miRNA and development of periodontitis and helping to better understand the pathobiology of periodontitis. Full article

(This article belongs to the Special Issue MicroRNAs in Periodontal Disease and Systemic Diseases)

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18 pages, 1390 KiB

Open AccessArticle

Global Noncoding microRNA Profiling in Mice Infected with Partial Human Mouth Microbes (PAHMM) Using an Ecological Time-Sequential Polybacterial Periodontal Infection (ETSPPI) Model Reveals Sex-Specific Differential microRNA Expression

by Chairmandurai Aravindraja, Matteen R. Kashef, Krishna Mukesh Vekariya, Ravi K. Ghanta, Shama Karanth, Edward K. L. Chan and Lakshmyya Kesavalu

Int. J. Mol. Sci. 2022, 23(9), 5107; https://doi.org/10.3390/ijms23095107 - 04 May 2022

Cited by 3 | Viewed by 2211

Abstract

Periodontitis (PD) is a polymicrobial dysbiotic immuno-inflammatory disease. It is more prevalent in males and has poorly understood pathogenic molecular mechanisms. Our primary objective was to characterize alterations in sex-specific microRNA (miRNA, miR) after periodontal bacterial infection. Using partial human mouth microbes (PAHMM) (Streptococcus gordonii, Fusobacterium nucleatum, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) in an ecological time-sequential polybacterial periodontal infection (ETSPPI) mouse model, we evaluated differential mandibular miRNA profiles by using high-throughput Nanostring nCounter^® miRNA expression panels. All PAHMM mice showed bacterial colonization (100%) in the gingival surface, an increase in alveolar bone resorption (p < 0.0001), and the induction of a specific immunoglobin G antibody immune response (p < 0.001). Sex-specific differences in distal organ bacterial dissemination were observed in the heart (82% male vs. 28% female) and lungs (2% male vs. 68% female). Moreover, sex-specific differential expression (DE) of miRNA was identified in PAHMM mice. Out of 378 differentially expressed miRNAs, we identified seven miRNAs (miR-9, miR-148a, miR-669a, miR-199a-3p, miR-1274a, miR-377, and miR-690) in both sexes that may be implicated in the pathogenesis of periodontitis. A strong relationship was found between male-specific miR-377 upregulation and bacterial dissemination to the heart. This study demonstrates sex-specific differences in bacterial dissemination and in miRNA differential expression. A novel PAHMM mouse and ETSPPI model that replicates human pathobiology can be used to identify miRNA biomarkers in periodontitis. Full article

(This article belongs to the Special Issue MicroRNAs in Periodontal Disease and Systemic Diseases)

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