Publications by authors named "Thomas E Van Dyke"

191 Publications

6-Shogaol promotes bone resorption and accelerates orthodontic tooth movement through the JNK-NFATc1 signaling axis.

J Bone Miner Metab 2021 Jun 30. Epub 2021 Jun 30.

Department of Oral and Cranio-Maxillofacial Surgery, Shanghai Key Laboratory of Stomatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Introduction: Corticotomy is widely used in clinical practice to accelerate tooth movement and shorten the duration of orthodontic treatment. It is effective, but an invasive surgery is needed to induce alveolar bone osteopenia that enable rapid tooth movement. In this study, we discovered the potential of 6-shogaol as a more patient-friendly non-invasive alternative to induce transient osteopenia and accelerate tooth movement.

Materials And Methods: The effects of 6-shogaol on the bone marrow macrophages (BMM) proliferation and osteoclast differentiation, and bone resorption were determined in vitro. Sprague-Dawley rats were distributed into three groups: CON, IPinj or Localinj and euthanized at day 28. Micro-CT, histology, immunohistological, and TUNEL analysis were performed to evaluate the tooth movement acceleration effect of 6-shogaol.

Results: In vitro, 6-shogaol promotes osteoclast differentiation and functional demineralization of alveolar bone. RANKL-induced mRNA expression of osteoclastic-specific genes was significantly higher in the presence of 6-shogaol. A dose-dependent increase in the area of TRAP-positive cells was observed with 6-shogaol treatment. F-actin ring formation and increased bone resorption confirmed that osteoclasts treated with 6-shogaol were mature and functional. 6-shogaol stimulated JNK activation and NFATc1 expression during osteoclast differentiation. In vivo, 6-shogaol promotes alveolar bone transient osteopenia and accelerates orthodontic tooth movement. Alveolar bone mass was reduced, more osteoclasts were observed in bone resorption lacunae on the compression side, and the expression of RANKL and sclerostin were higher than the control group. In conclusion, our results suggest that 6-shogoal accelerates tooth movement by inducing osteopenia by a mechanism similar to surgically induced bone injury.
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http://dx.doi.org/10.1007/s00774-021-01245-yDOI Listing
June 2021

Subgingival Microbiome and Specialized Pro-Resolving Lipid Mediator Pathway Profiles Are Correlated in Periodontal Inflammation.

Front Immunol 2021 10;12:691216. Epub 2021 Jun 10.

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, United States.

Failure of resolution pathways in periodontitis is reflected in levels of specialized pro-resolving lipid mediators (SPMs) and SPM pathway markers but their relationship with the subgingival microbiome is unclear. This study aimed to analyze and integrate lipid mediator level, SPM receptor gene expression and subgingival microbiome data in subjects with periodontitis vs. healthy controls. The study included 13 periodontally healthy and 15 periodontitis subjects that were evaluated prior to or after non-surgical periodontal therapy. Samples of gingival tissue and subgingival plaque were collected prior to and 8 weeks after non-surgical treatment; only once in the healthy group. Metabololipidomic analysis was performed to measure levels of SPMs and other relevant lipid mediators in gingiva. qRT-PCR assessed relative gene expression (2) of known SPM receptors. 16S rRNA sequencing evaluated the relative abundance of bacterial species in subgingival plaque. Correlations between lipid mediator levels, receptor gene expression and bacterial abundance were analyzed using the Data Integration Analysis for Biomarker discovery using Latent cOmponents (DIABLO) and Sparse Partial Least Squares (SPLS) methods. Profiles of lipid mediators, receptor genes and the subgingival microbiome were distinct in the three groups. The strongest correlation existed between lipid mediator profile and subgingival microbiome profile. Multiple lipid mediators and bacterial species were highly correlated (correlation coefficient ≥0.6) in different periodontal conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to healthy controls revealed that one bacterial species, , and five lipid mediators, 5(S)6(R)-DiHETE, 15(S)-HEPE, 7-HDHA, 13-HDHA and 14-HDHA, were identified in both conditions. Comparing individual correlated lipid mediators and bacterial species in periodontitis before treatment to after treatment revealed that one bacterial species, , and four lipid mediators, 5(S)12(S)-DiHETE, RvD1, Maresin 1 and LTB4, were identified in both conditions. Four species were highly correlated with RvD1, RvE3, 5(S)12(S)-DiHETE and proinflammatory mediators in the periodontitis after treatment group. Profiles of lipid mediators, receptor gene and subgingival microbiome are associated with periodontal inflammation and correlated with each other, suggesting inflammation mediated by lipid mediators influences microbial composition in periodontitis. The role of correlated individual lipid mediators and bacterial species in periodontal inflammation have to be further studied.
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http://dx.doi.org/10.3389/fimmu.2021.691216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222734PMC
June 2021

Transcriptomics of type 2 diabetic and healthy human neutrophils.

BMC Immunol 2021 Jun 16;22(1):37. Epub 2021 Jun 16.

Genomic Medicine and Infectious Diseases, J. Craig Venter Institute, 4120 Capricorn Lane, La Jolla, CA, 92037, USA.

Objectives: Chronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils.

Methods: Cell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction.

Results: We observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05).

Conclusions: The neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution.
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http://dx.doi.org/10.1186/s12865-021-00428-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207744PMC
June 2021

Exposure to Porphyromonas gingivalis and Modifiable Risk Factors Modulate Risk for Early Diabetic Retinopathy.

Transl Vis Sci Technol 2021 02;10(2):23

The Forsyth Institute, Cambridge, MA, USA.

Purpose: We hypothesized that exposure to Porphyromonas gingivalis (Pg) increases the risk for early diabetic retinopathy (DR) and that the risk can be modulated.

Methods: We identified 116 early DR cases, and 116 non-DR controls were selected randomly by frequency matching for age, sex, race, and education from the US Third National Health and Nutrition Examination Survey. DR was assessed using non-mydriatic fundus photographs and graded by trained graders using the Modified Airlie House Classification scheme and the Early Treatment for Diabetic Retinopathy Study severity scale. Serum Pg immunoglobulin G (IgG) antibody (Ab) was measured in enzyme-linked immunosorbent assay units. Logistic regression was used to relate serum Pg IgG Ab levels to the risk for early DR.

Results: Per tenfold increase in Pg IgG Ab levels, there was an over 60% increased risk for early DR (odds ratio = 1.64; 95% confidence interval, 1.36-1.97), and a linear trend was noted for the estimated probabilities of early DR at various Pg IgG Ab levels (P for trend = 0.0053). The analysis also suggested that moderate alcohol consumption (less than 12 drinks in the past 12 months; P for interaction = 0.0003) and maintaining a normal serum glycated hemoglobulin level (HbA1c ≤ 5.7%; P for interaction < 0.0001) helped reduce the Pg-related DR risk.

Conclusions: The increased Pg-related DR risk could be alleviated by managing alcohol consumption and maintaining a normal blood glucose level.

Translational Relevance: Findings from this study provide new directions for developing novel therapeutics and prevention strategies for DR.
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http://dx.doi.org/10.1167/tvst.10.2.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900844PMC
February 2021

A Novel Animal Model for Simulating Scarring After Cleft Lip Repair.

Facial Plast Surg Aesthet Med 2021 Feb 24. Epub 2021 Feb 24.

Department of Otolaryngology-Head and Neck Surgery, Tufts University School of Medicine, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1089/fpsam.2020.0525DOI Listing
February 2021

Use of amnion-derived cellular cytokine solution for the treatment of gingivitis: A 2-week safety, dose-ranging, proof-of-principle randomized trial.

J Periodontol 2021 Feb 15. Epub 2021 Feb 15.

The Forsyth Institute, Center for Clinical and Translational Research, Cambridge, MA.

Background: A 6-week Phase I clinical trial was performed to primarily evaluate the safety and secondarily determine the preliminary efficacy of a novel biological solution, ST266, comprised of a mixture of cytokines, growth factors, nucleic acids, and lipids secreted by cultured amnion-derived multipotent progenitor cells on gingival inflammation.

Methods: Fifty-four adults with gingivitis/periodontitis were randomly assigned to 1X ST266 or diluted 0.3X ST266 or saline topically applied on facial/lingual gingiva (20 µL/tooth). Safety was assessed through oral soft/hard tissue exam, adverse events, and routine laboratory tests. Efficacy was assessed by modified gingival index (MGI), bleeding on probing, plaque index, probing depth (PD), and clinical attachment level (CAL). Assessments were performed on day 0, 8, 12, and 42. ST266 and saline applied daily starting at day 0 through day 12 except weekend days. Plasma was analyzed for safety and proinflammatory cytokines, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, and interferon gamma. Gingival crevicular fluid (GCF) was analyzed for the same cytokines. Subgingival plaque was primarily analyzed by checkerboard DNA-DNA hybridization. Comparisons with saline were modeled through a generalized estimating equations method adjusting for baseline.

Results: No safety concern was found related to ST266. Statistically significant reduction in MGI was noted at day 42 by 1X ST266 compared with saline (P = 0.044). PD and CAL were reduced by both doses of ST266 at day 42 (P <0.01) and by 1X ST266 at day 12 (P <0.05). GCF IL-1β and IL-6 levels were reduced by both doses of ST266 at day 12 (P <0.05, P <0.01, respectively). IL-6 was also significantly reduced in plasma of both ST266 groups (P <0.05). Significant reductions in red complex bacteria were detected in both ST266 doses.

Conclusions: In this "first in human oral cavity" study, topical ST266 was safe and effective in reducing gingival inflammation in 6 weeks. Longitudinal studies with large sample sizes are warranted to assess the therapeutic value of this novel host modulatory compound in the treatment of periodontal diseases.
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http://dx.doi.org/10.1002/JPER.20-0800DOI Listing
February 2021

TLR2 and TLR4 Differentially Regulate the Osteogenic Capacity of Human Periodontal Ligament Fibroblasts.

J Int Acad Periodontol 2021 01 1;23(1):3-10. Epub 2021 Jan 1.

Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, MA, USA. E-mail address:

Aims: To test that the osteogenic capacity of periodontal ligament (PDL) fibroblasts can be mediated by TLR2 and TLR4 activation.

Materials And Methods: Human PDL fibroblasts were cultured in osteogenic medium and treated with TLR2 and TLR4 agonists (Pam3CSK4 and monophosphoryl Lipid A (MPLA), respectively). Cell proliferation was measured by MTT and BrdU incorporation. Osteogenic differentiation was measured by alkaline phosphatase (ALP) activity. Nodule formation was measured for osteoblast function. The expression of markers of potential signaling pathways (RUNX2, OCN, BSP and Osterix) was evaluated by quantitative PCR.

Results: PDL fibroblasts grew at the same rate during the first 5 days in response to both Pam3CSK5 and MPLA. On day 7, cells cultured in the presence of Pam3CSK4 had a significantly higher rate of DNA replication, while cells in MPLA group had a significantly lower DNA replication rate (one-third) compared to the control (p less than 0.05). Pam3CSK4 induced significantly higher ALP activity and larger calcified nodules. TLR4 activation significantly reduced the expression of RUNX2 and osterix and enhanced OCN. Neither TLR2 nor TLR4 affected BSP expression.

Conclusions: These data suggest that the activation of TLR2 and TLR4 differentially and perhaps antagonistically modulate osteogenesis by human PDL fibroblasts and have a direct role of TLR-mediated PDL function during periodontal regeneration as a potential target for therapeutics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142849PMC
January 2021

Inflammation of the periodontium associates with risk of future cardiovascular events.

J Periodontol 2021 03 13;92(3):348-358. Epub 2021 Feb 13.

Cardiovascular Imaging Research Center, Boston, MA.

Background: While growing evidence suggests a link between periodontal disease (PD) and cardiovascular disease (CVD), the independence of this association and the pathway remain unclear. Herein, we tested the hypotheses that: (1) inflammation of the periodontium (PD ) predicts future CVD independently of disease risk factors shared between CVD and PD, and (2) the mechanism linking the two diseases involves heightened arterial inflammation.

Methods: F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG-PET/CT) imaging was performed in 304 individuals (median age 54 years; 42.4% male) largely for cancer screening; individuals without active cancer were included. PD and arterial inflammation were quantified using validated F-FDG-PET/CT methods. Additionally, we evaluated the relationship between PD and subsequent major adverse cardiovascular events (MACE) using Cox models and log-rank tests.

Results: Thirteen individuals developed MACE during follow-up (median 4.1 years). PD associated with arterial inflammation, remaining significant after adjusting for PD and CVD risk factors (standardized β [95% CI]: 0.30 [0.20-0.40], P < 0.001). PD predicted subsequent MACE (standardized HR [95% CI]: 2.25 [1.47 to 3.44], P <0.001, remaining significant in multivariable models), while periodontal bone loss did not. Furthermore, mediation analysis suggested that arterial inflammation accounts for 80% of the relationship between PD and MACE (standardized log odds ratio [95% CI]: 0.438 [0.019-0.880], P = 0.022).

Conclusion: PD is independently associated with MACE via a mechanism that may involve increased arterial inflammation. These findings provide important support for an independent relationship between PD and CVD.
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http://dx.doi.org/10.1002/JPER.19-0441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080258PMC
March 2021

Maresin-1 and Resolvin E1 Promote Regenerative Properties of Periodontal Ligament Stem Cells Under Inflammatory Conditions.

Front Immunol 2020 25;11:585530. Epub 2020 Sep 25.

The Forsyth Institute, Cambridge, MA, United States.

Maresin-1 (MaR1) and Resolvin E1 (RvE1) are specialized pro-resolving lipid mediators (SPMs) that regulate inflammatory processes. We have previously demonstrated the hard and soft tissue regenerative capacity of RvE1 in an model of the periodontal disease characterized by inflammatory tissue destruction. Regeneration of periodontal tissues requires a well-orchestrated process mediated by periodontal ligament stem cells. However, limited data are available on how SPMs can regulate the regenerative properties of human periodontal ligament stem cells (hPDLSCs) under inflammatory conditions. Thus, we measured the impact of MaR1 and RvE1 in an model of hPDLSC under stimulation with IL-1β and TNF-α by evaluating pluripotency, migration, viability/cell death, periodontal ligament markers (α-smooth muscle actin, tenomodulin, and periostin), cementogenic-osteogenic differentiation, and phosphoproteomic perturbations. The data showed that the pro-inflammatory milieu suppresses pluripotency, viability, and migration of hPDLSCs; MaR1 and RvE1 both restored regenerative capacity by increasing hPDLSC viability, accelerating wound healing/migration, and up-regulating periodontal ligament markers and cementogenic-osteogenic differentiation. Protein phosphorylation perturbations were associated with the SPM-induced regenerative capacity of hPDLSCs. Together, these results demonstrate that MaR1 and RvE1 restore or improve the regenerative properties of highly specialized stem cells when inflammation is present and offer opportunities for direct pharmacologic treatment of lost tissue integrity.
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http://dx.doi.org/10.3389/fimmu.2020.585530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546375PMC
June 2021

Investigating the Response of Human Neutrophils to Hydrophilic and Hydrophobic Micro-Rough Titanium Surfaces.

Materials (Basel) 2020 Aug 3;13(15). Epub 2020 Aug 3.

Department of Periodontics, Indiana University School of Dentistry, Indianapolis, IN 46202, USA.

Various treatments have been used to change both the topography and chemistry of titanium surfaces, aiming to enhance tissue response and reduce healing times of endosseous implants. Most studies to date focused on bone healing around dental implants occurring later during the healing cascade. However, the impact of the initial inflammatory response in the surgical wound site on the success and healing time of dental implants is crucial for implant integration and success, yet it is still poorly understood. The purpose of this study was to investigate the effect of titanium surface hydrophilicity on the response of human neutrophils by monitoring oxygen radical production, which was measured as chemiluminescence activity. Materials and Methods: Neutrophils were isolated from human donors' blood buffy coats using the double sucrose gradient method. Neutrophils were exposed to both hydrophilic and hydrophobic titanium surfaces with identical topographies in the presence and absence of human serum. This resulted in six experimental groups including two different implant surfaces, with and without exposure to human serum, and two control groups including an active control with cells alone and a passive control with no cells. Two samples from each group were fixed and analyzed by SEM. Comparisons between surface treatments for differences in chemiluminescence values were performed using analysis of variance ANOVA. Results and Conclusion: In the absence of exposure to serum, there was no significant difference noted between the reaction of neutrophils to hydrophilic and hydrophobic surfaces. However, there was a significant reduction in the mean and active chemiluminescence activity of neutrophils to serum-coated hydrophilic titanium surfaces than to serum-coated hydrophobic titanium surfaces. This suggests that surface hydrophilicity promotes enhanced adsorption of serum proteins, which leads to decreased provocation of initial immune cells and reduction of local oxygen radical production during wound healing. This can help explain the faster osseointegration demonstrated by hydrophilic titanium implants.
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http://dx.doi.org/10.3390/ma13153421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435731PMC
August 2020

Distinct Profiles of Specialized Pro-resolving Lipid Mediators and Corresponding Receptor Gene Expression in Periodontal Inflammation.

Front Immunol 2020 25;11:1307. Epub 2020 Jun 25.

Department of Periodontics and Dental Hygiene, The University of Texas Health Science Center at Houston School of Dentistry, Houston, TX, United States.

Polyunsaturated fatty acid-derived specialized pro-resolving lipid mediators (SPMs) play an important role in modulating inflammation. The aim of the study was to compare profiles of SPMs, SPM related lipid mediators and SPM receptor gene expression in gingiva of subjects with periodontitis to healthy controls. A total of 28 subjects were included; 13 periodontally healthy and 15 periodontitis before or after non-surgical periodontal therapy. Gingival tissues were collected from two representative posterior teeth prior to and 8 weeks after scaling and root planning; only once in the healthy group. Lipid mediator-SPM metabololipidomics was performed to identify metabolites in gingiva. qRT-PCR was performed to assess relative gene expression (2) of known SPM receptors. Intergroup comparisons were made using Wilcoxon tests. Thirty-six omega-6 or omega-3 fatty acid-derived lipid mediators and seven receptor genes were identified in gingiva. Profiles of lipid mediators and receptor gene expression were significantly different between the three groups. Levels of six lipid mediators, 5-HETE, 15-HETE, 15(S)-HEPE, 4-HDHA, 7-HDHA, and 17-HDHA in periodontitis before treatment were significantly higher than in periodontitis after treatment. The expression of in the healthy group was significantly higher than periodontitis subjects before and after treatment. The expression of in periodontitis before treatment was significantly higher than in periodontitis after treatment while the expression of in periodontitis before treatment was significantly lower than in periodontitis after treatment. Elevated levels of SPM biosynthetic pathway markers in periodontitis subjects before treatment indicated inflammation induced pro-resolution activity in gingiva, but receptors for these molecules were deficient in periodontitis pre-treatment suggesting that failure of resolution of inflammation contributes to excess, chronic inflammation in periodontitis.
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http://dx.doi.org/10.3389/fimmu.2020.01307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330171PMC
April 2021

Steven Offenbacher, DDS, PhD, MMSc: The gifts of a giant in science and the father of periodontal medicine.

J Periodontol 2020 10;91 Suppl 1:S1-S3

The Forsyth Institute, Cambridge, MA.

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http://dx.doi.org/10.1002/JPER.20-0494DOI Listing
October 2020

Shifting the paradigm from inhibitors of inflammation to resolvers of inflammation in periodontitis.

J Periodontol 2020 10 20;91 Suppl 1:S19-S25. Epub 2020 Jun 20.

Clinical and Translational Research, Forsyth Institute, Cambridge, MA.

An initial shift in our understanding of the basis of periodontal disease occurred early in the 2000s. The host response, rather than the bacterial burden, was the principal determinant of the disease. Microbial dysbiosis that occurs in periodontal disease results from a hyperinflammatory state in the host. A second shift in periodontal disease is taking place. This time in the realm of treatment strategies. Rather than targeting antimicrobials or inhibitors of individual inflammatory mediators, preclinical studies support using resolution pharmacology to convert the pro-inflammatory condition into a non-inflammatory one, thereby resolving both the local and systemic inflammation associated with periodontal disease. Here, I describe the bases for these shifts in paradigms.
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http://dx.doi.org/10.1002/JPER.20-0088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142079PMC
October 2020

Activation of PPAR-γ induces macrophage polarization and reduces neutrophil migration mediated by heme oxygenase 1.

Int Immunopharmacol 2020 Jul 7;84:106565. Epub 2020 May 7.

Faculdade São Leopoldo Mandic, Instituto de Pesquisas São Leopoldo Mandic, Laboratoy of Neuroimmune Interface of Pain Research, Campinas, SP, Brazil; Department of Physiology Sciences, Laboratory of Orofacial Pain, Piracicaba Dental School, University of Campinas - UNICAMP, Piracicaba, SP, Brazil. Electronic address:

Natural or synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ) represent an interesting tool for pharmacological interventions to treat inflammatory conditions. In particular, PPAR-γ activation prevents pain and inflammation in the temporomandibular joint (TMJ) by decreasing cytokine release and stimulating the synthesis of endogenous opioids. The goal of this study was to clarify whether PPAR-γ activation induces macrophage polarization, inhibiting inflammatory cytokine release and leukocyte recruitment. In addition, we investigated the involvement of heme oxygenase 1 (HO-1) in downstream events after PPAR-γ activation. Our results demonstrate that PPAR-γ activation ablates cytokine release by Bone Marrow-Derived Macrophages (BMDM) in vitro. 15d-PGJ induces the PPAR-γ heterodimer activation from rat macrophages, with macrophage polarization from M1-like cells toward M2-like cells. This response is mediated through HO-1. PPAR-γ activation diminished neutrophil migration induced by carrageenan, which was also HO-1 dependent. Ca/calmodulin expression did not change after PPAR-γ activation indicating that is not required for the activation of the intracellular L-arginine/NO/cGMP/K channel pathway. In summary, the anti-inflammatory actions induced by PPAR-γ activation involve macrophage polarization. HO-1 expression is increased and HO-1 activity is required for the suppression of neutrophil migration.
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http://dx.doi.org/10.1016/j.intimp.2020.106565DOI Listing
July 2020

The role of the microbiota in periodontal disease.

Periodontol 2000 2020 06;83(1):14-25

Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA.

The last decade has witnessed unparalleled advances in our understanding of the complexity of the oral microbiome and the compositional changes that occur in subgingival biofilms in the transition from health to gingivitis and to destructive periodontal disease. The traditional view, which has held sway for the last 2 decades, that disease is characterized by the outgrowth of a consortium, or consortia, of a limited number of potentially pathogenic organisms, has given way to an alternative paradigm. In this new view, the microbiological changes associated with disease represent whole-scale alterations to the overall microbial population structure and to the functional properties of the entire community. Thus, and in common with other microbially mediated diseases of the gastrointestinal tract, the normally balanced, symbiotic, and generally benign commensal microbiome of the tooth-associated biofilm undergoes dysbiosis to a potentially deleterious microbiota. Coincident with progress in defining the microbiology of these diseases, there have been equally important advances in our understanding of the inflammatory systems of the periodontal tissues, their control, and how inflammation may contribute both to the development of dysbiosis and, in a deregulated state, the destructive disease process. One can therefore speculate that the inflammatory response and the periodontal microbiome are in a bidirectional balance in oral health and a bidirectional imbalance in periodontitis. However, despite these clear insights into both sides of the host/microbe balance in periodontal disease, there remain several unresolved issues concerning the role of the microbiota in disease. These include, but are not limited to, the factors which determine progression from gingivitis to periodontitis in a proportion of the population, whether dysbiosis causes disease or results from disease, and the molecular details of the microbial stimulus responsible for driving the destructive inflammatory response. Further progress in resolving these issues may provide significant benefit to diagnosis, treatment, and prevention.
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http://dx.doi.org/10.1111/prd.12296DOI Listing
June 2020

The role of inflammation and genetics in periodontal disease.

Periodontol 2000 2020 06;83(1):26-39

Center for Clinical and Translational Research, Forsyth Institute, Cambridge, Massachusetts, USA.

Periodontitis is a complex disease: (a) various causative factors play a role simultaneously and interact with each other; and (b) the disease is episodic in nature, and bursts of disease activity can be recognized, ie, the disease develops and cycles in a nonlinear fashion. We recognize that various causative factors determine the immune blueprint and, consequently, the immune fitness of a subject. Normally, the host lives in a state of homeostasis or symbiosis with the oral microbiome; however, disturbances in homeostatic balance can occur, because of an aberrant host response (inherited and/or acquired during life). This imbalance results from hyper- or hyporesponsiveness and/or lack of sufficient resolution of inflammation, which in turn is responsible for much of the disease destruction seen in periodontitis. The control of this destruction by anti-inflammatory processes and proresolution processes limits the destruction to the tissues surrounding the teeth. The local inflammatory processes can also become systemic, which in turn affect organs such as the heart. Gingival inflammation also elicits changes in the ecology of the subgingival environment providing optimal conditions for the outgrowth of gram-negative, anaerobic species, which become pathobionts and can propagate periodontal inflammation and can further negatively impact immune fitness. The factors that determine immune fitness are often the same factors that determine the response to the resident biofilm, and are clustered as follows: (a) genetic and epigenetic factors; (b) lifestyle factors, such as smoking, diet, and psychosocial conditions; (c) comorbidities, such as diabetes; and (d) local and dental factors, as well as randomly determined factors (stochasticity). Of critical importance are the pathobionts in a dysbiotic biofilm that drive the viscious cycle. Focusing on genetic factors, currently variants in at least 65 genes have been suggested as being associated with periodontitis based on genome-wide association studies and candidate gene case control studies. These studies have found pleiotropy between periodontitis and cardiovascular diseases. Most of these studies point to potential pathways in the pathogenesis of periodontal disease. Also, most contribute to a small portion of the total risk profile of periodontitis, often limited to specific racial and ethnic groups. To date, 4 genetic loci are shared between atherosclerotic cardiovascular diseases and periodontitis, ie, CDKN2B-AS1(ANRIL), a conserved noncoding element within CAMTA1 upstream of VAMP3, PLG, and a haplotype block at the VAMP8 locus. The shared genes suggest that periodontitis is not causally related to atherosclerotic diseases, but rather both conditions are sequelae of similar (the same?) aberrant inflammatory pathways. In addition to variations in genomic sequences, epigenetic modifications of DNA can affect the genetic blueprint of the host responses. This emerging field will yield new valuable information about susceptibility to periodontitis and subsequent persisting inflammatory reactions in periodontitis. Further studies are required to verify and expand our knowledge base before final cause and effect conclusions about the role of inflammation and genetic factors in periodontitis can be made.
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http://dx.doi.org/10.1111/prd.12297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319430PMC
June 2020

The Nexus Between Periodontal Inflammation and Dysbiosis.

Front Immunol 2020 31;11:511. Epub 2020 Mar 31.

Melbourne Dental School, The University of Melbourne, Melbourne, VIC, Australia.

The nexus between periodontal inflammation and the polymicrobial biofilm in the gingival sulcus is critical to understanding the pathobiology of periodontitis. Both play a major role in the etiology and pathogenesis of periodontal diseases and each reinforces the other. However, this nexus is also at the center of a significant conundrum for periodontology. For all mucosal polymicrobial biofilms, the most confounding issue is the paradoxical relationship between inflammation, infection, and disease. Despite significant advances made in both periodontal microbiology and periodontal pathobiology, the issue of which comes first, the inflammatory response or the change to a dysbiotic subgingival microbiota, is still debated. In this paper, we present a model for the pathogenesis of periodontitis based on the central role of inflammation and how this modulates the polymicrobial biofilm within the context of the continuum of health, gingivitis, and periodontitis. We propose a new model termed "Inflammation-Mediated Polymicrobial-Emergence and Dysbiotic-Exacerbation" (IMPEDE), which is designed to integrate into and complement the 2017 World Workshop Classification of Periodontitis.
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http://dx.doi.org/10.3389/fimmu.2020.00511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136396PMC
March 2021

Periodontitis: a host mediated disruption of microbial homeostasis.

Curr Oral Health Rep 2020 Mar 25;7(1):3-11. Epub 2020 Jan 25.

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA.

Purpose Of Review: In a prolific scientific career, Dr. Robert J. Genco dedicated himself to enriching our understanding of the pathogenesis of periodontitis. During a period of time in the 1970s and 1980s, when periodontitis was considered a classic infectious disease, Bob had the foresight to investigate and characterize the immune/inflammatory response in periodontitis, particularly Juvenile Periodontitis. His leadership in this area brought to the fore our appreciation of host-microbiome interactions that many years later (2008) culminated in the realization that periodontitis is a fundamental inflammatory disease. In this review, the question of how the host regulates the inflammatory response will be addressed in the context of how more recently-discovered pathways of resolution of inflammation play a role in disease pathogenesis.

Recent Findings: The host inflammatory response to commensal organisms creates excess inflammation in susceptible individuals and likely drives the dysbiosis of the oral microbiome observed in people with Periodontitis. In periodontal health, the oral microbiome is in balance with the host response. It is the loss of this symbiotic relationship with excess inflammation and microbiome dysbiosis that characterizes progressive disease. In recent years, the role of mediators of resolution of inflammation in the loss of balance and their potential use as therapeutics to restore homeostasis has extended our knowledge of how the host drives immune responses to affect oral dysbiosis.

Summary: Dr. Genco provided the foundation for our ever-emerging understanding host-microbial interactions. The discovery of inflammation resolution pathways has furthered our knowledge in periodontal homeostasis. More studies are needed to understand how the host regulates the microbiome to fulfill the ultimate goal of more efficient therapeutics for periodontitis and related inflammatory diseases.
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http://dx.doi.org/10.1007/s40496-020-00256-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189440PMC
March 2020

Omega-3 PUFA and aspirin as adjuncts to periodontal debridement in patients with periodontitis and type 2 diabetes mellitus: Randomized clinical trial.

J Periodontol 2020 10 21;91(10):1318-1327. Epub 2020 Jun 21.

Division of Periodontics, Unesp - São Paulo State University, Institute of Science and Technology, São José dos Campos, São Paulo, Brazil.

Background: Supplementation with omega-3 polyunsaturated fatty acids (ω-3 PUFA) and low-dose aspirin (ASA) have been proposed as a host modulation regimen to control chronic inflammatory diseases. The aim of this study was to investigate the clinical and immunological impact of orally administered ω-3 PUFA and ASA as adjuncts to periodontal debridement for the treatment of periodontitis in patients type 2 diabetes.

Methods: Seventy-five patients (n = 25/group) were randomly assigned to receive placebo and periodontal debridement (CG), ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) after periodontal debridement (test group [TG]1), or ω-3 PUFA + ASA (3 g of fish oil/d + 100 mg ASA/d for 2 months) before periodontal debridement (TG2). Periodontal parameters and GCF were collected at baseline (t0), 3 months after periodontal debridement and ω-3 PUFA + ASA or placebo for TG1 and CG (t1), after ω-3 PUFA + ASA (before periodontal debridement) for TG2 (t1), and 6 months after periodontal debridement (all groups) (t2). GCF was analyzed for cytokine levels by multiplex ELISA.

Results: Ten patients (40%) in TG1 and nine patients (36%) in TG2 achieved the clinical endpoint for treatment (less than or equal to four sites with probing depth ≥ 5 mm), as opposed to four (16%) in CG. There was clinical attachment gain in moderate and deep pockets for TG1. IFN-γ and interleukin (IL)-8 levels decreased over time for both test groups. IL-6 levels were lower for TG1. HbA1c levels reduced for TG1.

Conclusion: Adjunctive ω-3 and ASA after periodontal debridement provides clinical and immunological benefits to the treatment of periodontitis in patients with type 2 diabetes.
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http://dx.doi.org/10.1002/JPER.19-0613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483813PMC
October 2020

Understanding resolution of inflammation in periodontal diseases: Is chronic inflammatory periodontitis a failure to resolve?

Periodontol 2000 2020 02;82(1):205-213

Harvard School of Dental Medicine, Boston, Massachusetts, USA.

Periodontitis is an infectious-inflammatory disease that results from loss of balance between the commensal microbiome and the host response. The hyper-inflammatory, uncontrolled inflammatory immune lesion promotes tissue damage and impedes effective bacterial clearance. In this review, the relationship between the microbiome and the inflammatory/immune response is explored in the context of a bi-directional pathogenesis; bacteria induce inflammation and inflammation modifies the growth environment causing shifts in the composition of the microbiome. Resolution of inflammation is an active, receptor-mediated process induced by specialized pro-resolving lipid mediators. Inflammatory disease may, therefore, be the result of failure of resolution. Failure to resolve inflammation coupled with resultant microbiome changes is hypothesized to drive development of periodontitis. Re-establishment of microbiome/host homeostasis by specialized pro-resolving lipid mediator therapy suggests that microbiome dysbiosis, the host hyperinflammatory phenotype, and periodontitis can be reversed.
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http://dx.doi.org/10.1111/prd.12317DOI Listing
February 2020

Omega-3 Fatty Acids Effects on Inflammatory Biomarkers and Lipid Profiles among Diabetic and Cardiovascular Disease Patients: A Systematic Review and Meta-Analysis.

Sci Rep 2019 12 11;9(1):18867. Epub 2019 Dec 11.

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA, USA.

The purpose of this systematic review and meta-analysis was to investigate omega-3 fatty acids' influence on 12 inflammatory biomarkers-LDL, HDL, total cholesterol, TG, HbA1c, Apo AI, Apo AII, Apo B, CRP, TNF-α, glucose, and fasting blood glucose among diabetic and cardiovascular disease (CVD) patients. We searched articles in six database engines, and 16 of the 696 articles reviewed met the inclusion criteria. Among these, lipid and inflammatory biomarkers investigated commonly included total cholesterol (11 studies), LDL, and TG (10 studies each). Overall, omega-3 was associated with a significant reduction in Apo AII among diabetic patients, as compared to different controls (-8.0 mg/dL 95% CI: -12.71, -3.29, p = 0.0009), triglycerides (-44.88 mg/dL 95% CI: -82.6, -7.16, p < 0.0001), HDL (-2.27 mg/dL 95% CI: -3.72, -0.83, p = 0.002), and increased fasting blood glucose (16.14 mg/dL 95% CI: 6.25, 26.04, p = 0.001). Omega-3 also was associated with increased LDL among CVD patients (2.10 mg/dL 95% CI: 1.00, 3.20, p = 0.0002). We conclude that omega-3 fatty acids may be associated with lower inflammatory biomarkers among diabetic and cardiovascular patients. Clinicians should be aware of these potential benefits; however, it is essential to recommend that patients consult with clinicians before any omega-3 intake.
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http://dx.doi.org/10.1038/s41598-019-54535-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906408PMC
December 2019

Characterization of periodontitis in people with type 1 diabetes of 50 years or longer duration.

J Periodontol 2019 06 13;90(6):565-575. Epub 2019 May 13.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

Background: Periodontitis is more common and severe in people with diabetes than the general population. We have reported in the Joslin Medalist Study that people with type 1 diabetes of ≥50 years (Medalists) may have endogenous protective factors against diabetic nephropathy and retinopathy.

Methods: In this cross-sectional study, the prevalence of periodontitis according to the Centers for Disease Control/American Academy of Periodontology classification in a subset (n = 170, mean age = 64.6 ± 6.9 years) of the Medalist cohort, and its associations to various criteria of periodontitis and diabetic complications were assessed.

Results: The prevalence of severe periodontitis in Medalists was only 13.5% which was lower than reported levels in diabetic patients of similar ages. Periodontal parameters, including bleeding on probing, plaque index, gingival index, and demographic traits, including male sex, chronological age, and age at diagnosis were significantly associated with severity of periodontitis, which did not associate with diabetes duration, hemoglobin A1c (HbA1c), body mass index, and lipid profiles. Random serum C-peptide levels inversely associated with severity of periodontitis (P = 0.03), lower probing depth (P = 0.0002), and clinical attachment loss (P = 0.03). Prevalence of cardiovascular diseases (CVD) and systemic inflammatory markers, plasma interleukin-6 (IL-6), and serum immunoglobulin G titer against Porphyromonas gingivalis positively associated with severity of periodontitis (P = 0.002 and 0.02, respectively). Antibody titer to P. gingivalis correlated positively and significantly with CVD, serum IL-6, and high-sensitivity C-reactive protein.

Conclusions: Some Medalists could be protected from severe periodontitis even with hyperglycemia. Endogenous protective factors for periodontitis could possibly be related to residual insulin production and lower levels of chronic inflammation.
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http://dx.doi.org/10.1002/JPER.18-0735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087383PMC
June 2019

Resolvin D2 Induces Resolution of Periapical Inflammation and Promotes Healing of Periapical Lesions in Rat Periapical Periodontitis.

Front Immunol 2019 26;10:307. Epub 2019 Feb 26.

Department of Pathophysiology-Periodontal Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Periapical periodontitis results from pulpal infection leading to pulpal necrosis and resorption of periapical bone. The current treatment is root canal therapy, which attempts to eliminate infection and necrotic tissue. But, in some cases periapical inflammation doesn't resolve even after treatment. Resolvins belongs to a large family of specialized pro-resolving lipid mediators that actively resolves inflammation signaling via specific receptors. Resolvin D2 (RvD2), a metabolite of docosahexaenoic acid (DHA), was tested as an intracanal medicament in rats . Mechanism was evaluated in rat primary dental pulp cells (DPCs) . The results demonstrate that RvD2 reduces inflammatory cell infiltrate, periapical lesion size, and fosters pulp like tissue regeneration and healing of periapical lesion. RvD2 enhanced expression of its receptor, GPR18, dentin matrix acidic phosphoprotein 1 (DMP1) and mineralization and . Moreover, RvD2 induces phosphorylation of Stat3 transcription factor in dental pulp cells. We conclude that intracanal treatment with RvD2 resolves inflammation and promoting calcification around root apex and healing of periapical bone lesions. The data suggest that RvD2 induces active resolution of inflammation with pulp-like tissue regeneration after root canal infection and thus maybe suitable for treating periapical lesions.
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http://dx.doi.org/10.3389/fimmu.2019.00307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399419PMC
September 2020

Function of Pro-Resolving Lipid Mediator Resolvin E1 in Type 2 Diabetes.

Crit Rev Immunol 2018 ;38(5):343-365

Center for Clinical and Translational Research, The Forsyth Institute, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard Medical School, Boston, MA, 02115, USA.

Programming of inflammation resolution is governed by a class of specialized pro-resolving lipid mediators (SPMs) that act in concert to modulate epithelial, endothelial, and immune cell function for restoration of homeostasis. The resolution circuits are altered in obesity and associated morbidities, including type 2 diabetes mellitus (T2D), through reduced production and/or action of SPMs, which can be rescued by therapeutic SPM delivery or up-regulation of SPM receptors. Resolvin E1 (RvE1), an eicosapentaenoic acid derivative, has potent pro-resolving and insulin-sensitizing actions mediated by BLT1 and ERV1 receptors in the vasculature and metabolic organs. Nonetheless, the RvE1-mediated increase in protective adipokines such as adiponectin in white adipose tissues, the enhancement of monocyte patrolling function in the vasculature, as well as the macrophage-clearing functions improve metabolic control in obese-prone conditions. RvE1-enhanced resolving function in obesity prevents dysbiosis of the gut microflora and increased gut permeability. These functions suggest that RE1 has therapeutic potential for immunometabolic alterations associated with T2D in patients with reduced inflammation resolving capacity. SPM profiling in individuals at risk for T2D and associated complications will help to advance personalized disease management and precision medicine.
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http://dx.doi.org/10.1615/CritRevImmunol.2018026750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392080PMC
September 2019

Hypoxia-induced endothelial cell responses - possible roles during periodontal disease.

Clin Exp Dent Res 2018 Dec 14;4(6):241-248. Epub 2018 Dec 14.

Forsyth Institute MA USA.

Background and objective Inflammatory periodontal pockets are known to be hypoxic. Hypoxia influences vascular response to periodontal inflammation, including angiogenesis, which is critical for oxygen and nutrient delivery to periodontal tissues and granulation tissue formation. Our previous work suggests that periodontal bacteria may actively contribute to pocket hypoxia. Herein, we test the hypothesis that actively induces low oxygen tension, which modulates angiogenesis and endothelial cell activity. HUVEC cells were incubated in 1.5% oxygen for (Folkman & Shing, 1992)48 hours. Cell proliferation was measured by MTT; surface expression of CD31, CD34 and VEGF receptors (VEGFR1, VEGFR2) were analyzed by FACS. mRNA expression of HIF isoforms, iNOS, eNOS, COX-2, and VEGF was measured by quantitative PCR. Supernatants were analyzed for the release of IL-1α, TNF-α, and VEGF by ELISA or multiplex immunoassays and nitric oxide was measured by colorimetric assay. actively depleted oxygen. Hypoxia resulted in a significant increase of HIF isoforms. iNOS was increased while nitric oxide was unchanged. VEGF release was increased at 4 hours followed by an increase in VEGFR1 at 12 hours, but not VEGFR2. CD31 expression was reduced and CD34 was increased after 48 hours ( < 0.05). IL-1α and TNF-α release were decreased at 4 hours (p < 0.05), but both increased by 24 hours; TNF-α increased at 24 h. The data highlight the role of hypoxia in endothelial cell inflammatory changes. considered a bridging species in the development of periodontopathic biofilms induces hypoxia in the periodontium leading to angiogenic changes in periodontal disease pathogenesis.
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http://dx.doi.org/10.1002/cre2.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305913PMC
December 2018

An appraisal of the role of specific bacteria in the initial pathogenesis of periodontitis.

J Clin Periodontol 2019 01;46(1):6-11

Forsyth Institute, Cambridge, Massachusetts.

Background: Historically, inflammatory periodontal diseases (gingivitis and periodontitis) have been recognized as being primarily of bacterial origin. Bacteria are necessary for disease development, but the presence of specific bacteria does not guarantee progression to periodontitis. Periodontitis is a multifactorial disease; specific bacteria are associated with disease, but may not be the target of treatment. Gingivitis and periodontitis are inflammatory conditions associated with bacterial overgrowth.

Aim: To analyse evidence for established thought that specific bacteria directly participate in the pathogenesis of periodontitis and question the long-held tenet that penetration of the periodontal connective tissues by bacteria and their products is a significant phase in the initial development of periodontitis.

Methods: The literature was searched for studies on initiation of gingivitis and periodontitis by specific pathogens. The search results were insufficient for a systematic review and have been summarized in a commentary instead.

Results: There is very little evidence in the literature to support the commonly held concept that specific bacteria initiate periodontitis.

Conclusion: We present evidence for a paradigm supporting the central role of inflammation, rather than specific microbiota, in the early pathogenesis of periodontitis, and discuss whether controlling the inflammation can influence the character and composition of the periodontal infection.
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http://dx.doi.org/10.1111/jcpe.13046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357965PMC
January 2019

Resolvin E1 Promotes Bone Preservation Under Inflammatory Conditions.

Front Immunol 2018 12;9:1300. Epub 2018 Jun 12.

The Forsyth Institute, Cambridge, MA, United States.

Resolvins are endogenous lipid mediators derived from omega-3 fatty acids. Resolvin E1 (RvE1), derived from eicosapentaenoic acid (EPA), modulates osteoclasts and immune cells in periodontal disease models. The direct role of RvE1 in bone remodeling is not well understood. The objective of this study was to determine the impact of RvE1 on bone remodeling under inflammatory conditions. Our working hypothesis is that RvE1 downregulates bone resorption through direct actions on both osteoblast and osteoclast function in inflammatory osteoclastogenesis. A tumor necrosis factor-α induced local calvarial osteolysis model with or without the systemic administration of RvE1 was used. To evaluate osteoclastogenesis and NFκB signaling pathway activity, murine bone tissue was evaluated by Micro CT (μCT) analysis, TRAP staining, and immunofluorescence analysis. Mechanistically, to evaluate the direct role of RvE1 impacting bone cells, primary calvarial mouse osteoblasts were stimulated with interleukin (IL)-6 (10 ng/ml) and IL-6 receptor (10 ng/ml) and simultaneously incubated with or without RvE1 (100 nM). Expression of receptor activator of NFκB ligand (RANKL) and osteoprotegerin (OPG) was measured by ELISA. RNA sequencing (RNA-Seq) and differential expression analysis was performed to determine signaling pathways impacted by RvE1. The systemic administration of RvE1 reduced calvarial bone resorption as determined by µCT. Histologic analysis of calvaria revealed that osteoclastogenesis was reduced as determined by number and size of osteoclasts in TRAP-stained sections ( < 0.05). Immunofluorescence staining of calvarial sections revealed that RvE1 reduced RANKL secretion by 25% ( < 0.05). Stimulation of osteoblasts with IL-6 increased RANKL production by 30% changing the RANKL/OPG to favor osteoclast activation and bone resorption. The ratio changes were reversed by 100 nM RvE1. RvE1 decreased the production of RANKL maintaining an RANKL/OPG more favorable for bone formation. RNA-Seq and transcriptomic pipeline analysis revealed that RvE1 significantly downregulates osteoclast differentiation mediated by differential regulation of NFκB and PI3K-AKT pathways. RvE1 reduces inflammatory bone resorption. This action is mediated, at least in part, by direct actions on bone cells promoting a favorable RANKL/OPG ratio. Mediators of resolution in innate immunity also directly regulate bone cell gene expression that is modulated by RvE1 through at least 14 specific genes in this mouse model.
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http://dx.doi.org/10.3389/fimmu.2018.01300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005849PMC
August 2019

Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions.

J Periodontol 2018 06;89 Suppl 1:S74-S84

Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Japan.

Periodontal health is defined by absence of clinically detectable inflammation. There is a biological level of immune surveillance that is consistent with clinical gingival health and homeostasis. Clinical gingival health may be found in a periodontium that is intact, i.e. without clinical attachment loss or bone loss, and on a reduced periodontium in either a non-periodontitis patient (e.g. in patients with some form of gingival recession or following crown lengthening surgery) or in a patient with a history of periodontitis who is currently periodontally stable. Clinical gingival health can be restored following treatment of gingivitis and periodontitis. However, the treated and stable periodontitis patient with current gingival health remains at increased risk of recurrent periodontitis, and accordingly, must be closely monitored. Two broad categories of gingival diseases include non-dental plaque biofilm-induced gingival diseases and dental plaque-induced gingivitis. Non-dental plaque biofilm-induced gingival diseases include a variety of conditions that are not caused by plaque and usually do not resolve following plaque removal. Such lesions may be manifestations of a systemic condition or may be localized to the oral cavity. Dental plaque-induced gingivitis has a variety of clinical signs and symptoms, and both local predisposing factors and systemic modifying factors can affect its extent, severity, and progression. Dental plaque-induced gingivitis may arise on an intact periodontium or on a reduced periodontium in either a non-periodontitis patient or in a currently stable "periodontitis patient" i.e. successfully treated, in whom clinical inflammation has been eliminated (or substantially reduced). A periodontitis patient with gingival inflammation remains a periodontitis patient (Figure 1), and comprehensive risk assessment and management are imperative to ensure early prevention and/or treatment of recurrent/progressive periodontitis. Precision dental medicine defines a patient-centered approach to care, and therefore, creates differences in the way in which a "case" of gingival health or gingivitis is defined for clinical practice as opposed to epidemiologically in population prevalence surveys. Thus, case definitions of gingival health and gingivitis are presented for both purposes. While gingival health and gingivitis have many clinical features, case definitions are primarily predicated on presence or absence of bleeding on probing. Here we classify gingival health and gingival diseases/conditions, along with a summary table of diagnostic features for defining health and gingivitis in various clinical situations.
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http://dx.doi.org/10.1002/JPER.17-0719DOI Listing
June 2018
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