International Journal of Molecular Sciences

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3 pages, 185 KiB

Open AccessEditorial

Molecular Mechanisms of Periodontal Disease

by Mikihito Kajiya and Hidemi Kurihara

Int. J. Mol. Sci. 2021, 22(2), 930; https://doi.org/10.3390/ijms22020930 - 19 Jan 2021

Cited by 15 | Viewed by 2957

Abstract

Periodontal disease, one of the most prevalent human infectious diseases, is characterized by chronic inflammatory tissue destruction of the alveolar bone and the connective tissues supporting the tooth [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

Research

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18 pages, 12052 KiB

Open AccessArticle

Allicin May Promote Reversal of T-Cell Dysfunction in Periodontitis via the PD-1 Pathway

by Shankargouda Patil, Mohammed E. Sayed, Maryam H. Mugri, Khalaf F. Alsharif, Arif Salman, Shilpa Bhandi, Hosam Ali Baeshen, Thodur Madapusi Balaji, Pradeep Kumar Yadalam, Saranya Varadarajan, R. Srimathi R. Radha, Kamran Habib Awan, Vikrant R. Patil and A. Thirumal Raj

Int. J. Mol. Sci. 2021, 22(17), 9162; https://doi.org/10.3390/ijms22179162 - 25 Aug 2021

Cited by 6 | Viewed by 2792

Abstract

We evaluated the role of allicin in periodontitis using an in silico and in vitro design. An in silico docking analysis was performed to assess the plausible interactions between allicin and PD-L1. The cytokine profile of gingival crevicular fluid (GCF) samples obtained [...] Read more.

We evaluated the role of allicin in periodontitis using an in silico and in vitro design. An in silico docking analysis was performed to assess the plausible interactions between allicin and PD-L1. The cytokine profile of gingival crevicular fluid (GCF) samples obtained from periodontitis patients was estimated by cytometric bead array. CD3+ lymphocytes isolated from the peripheral blood were sorted and characterized using immunomagnetic techniques. Cultured and expanded lymphocytes were treated with the GCF samples to induce T-cell exhaustion. Optimum concentrations of allicin were added to exhausted lymphocytes to compare the expression of TIM-3 and LAG-3 gene expression at baseline and post-treatment. Allicin was found to bind to the PD-L1 molecule as revealed by the in-silico experiment, which is possibly an inhibitory interaction although not proven. GCF from periodontitis patients had significantly higher concentrations of TNF-α, CCL2, IL-6, IFN-γ, and CXCL8 than controls. GCF treatment of CD3+ lymphocytes from the periodontitis patients significantly increased expression of T-cell exhaustion markers TIM-3 and LAG-3. Allicin administration with GCF treatment resulted in significant lowering of the expression of exhaustion markers. Allicin may exert an immunostimulatory role and reverse immune-destructive mechanisms such as T-cell exhaustion. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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17 pages, 2926 KiB

Open AccessArticle

LAMP-2 Is Involved in Surface Expression of RANKL of Osteoblasts In Vitro

by Ineke D.C. Jansen, Wikky Tigchelaar-Gutter, Jolanda M. A. Hogervorst, Teun J. de Vries, Paul Saftig and Vincent Everts

Int. J. Mol. Sci. 2020, 21(17), 6110; https://doi.org/10.3390/ijms21176110 - 25 Aug 2020

Cited by 8 | Viewed by 3103

Abstract

Lysosome associated membrane proteins (LAMPs) are involved in several processes, among which is fusion of lysosomes with phagosomes. For the formation of multinucleated osteoclasts, the interaction between receptor activator of nuclear kappa β (RANK) and its ligand RANKL is essential. Osteoclast precursors express [...] Read more.

Lysosome associated membrane proteins (LAMPs) are involved in several processes, among which is fusion of lysosomes with phagosomes. For the formation of multinucleated osteoclasts, the interaction between receptor activator of nuclear kappa β (RANK) and its ligand RANKL is essential. Osteoclast precursors express RANK on their membrane and RANKL is expressed by cells of the osteoblast lineage. Recently it has been suggested that the transport of RANKL to the plasma membrane is mediated by lysosomal organelles. We wondered whether LAMP-2 might play a role in transportation of RANKL to the plasma membrane of osteoblasts. To elucidate the possible function of LAMP-2 herein and in the formation of osteoclasts, we analyzed these processes in vivo and in vitro using LAMP-2-deficient mice. We found that, in the presence of macrophage colony stimulating factor (M-CSF) and RANKL, active osteoclasts were formed using bone marrow cells from calvaria and long bone mouse bone marrow. Surprisingly, an almost complete absence of osteoclast formation was found when osteoclast precursors were co-cultured with LAMP-2 deficient osteoblasts. Fluorescence-activated cell sorting FACS analysis revealed that plasma membrane-bound RANKL was strongly decreased on LAMP-2 deficient osteoblasts. These results suggest that osteoblastic LAMP-2 is required for osteoblast-induced osteoclast formation in vitro. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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17 pages, 8326 KiB

Open AccessArticle

Detection of Salivary Small Extracellular Vesicles Associated Inflammatory Cytokines Gene Methylation in Gingivitis

by Pingping Han, Andrew Lai, Carlos Salomon and Sašo Ivanovski

Int. J. Mol. Sci. 2020, 21(15), 5273; https://doi.org/10.3390/ijms21155273 - 24 Jul 2020

Cited by 31 | Viewed by 3516

Abstract

Salivary small extracellular vesicles (sEV) are emerging as a potential liquid biopsy for oral diseases. However, technical difficulties for salivary sEV isolation remain a challenge. Twelve participants (five periodontally healthy, seven gingivitis patients) were recruited and salivary sEV were isolated by ultracentrifuge (UC-sEV) [...] Read more.

Salivary small extracellular vesicles (sEV) are emerging as a potential liquid biopsy for oral diseases. However, technical difficulties for salivary sEV isolation remain a challenge. Twelve participants (five periodontally healthy, seven gingivitis patients) were recruited and salivary sEV were isolated by ultracentrifuge (UC-sEV) and size exclusion chromatography (SEC-sEV). The effect of UC and SEC on sEV yield, DNA methylation of five cytokine gene promoters (interleukin (IL)−6, tumor necrosis factor (TNF)-α, IL−1β, IL−8, and IL−10), and functional uptake by human primary gingival fibroblasts (hGFs) was investigated. The results demonstrated that SEC-sEV had a higher yield of particles and particle/protein ratios compared to UC-sEV, with a minimal effect on the detection of DNA methylation of five cytokine genes and functional uptake in hGFs (n = 3). Comparing salivary sEV characteristics between gingivitis and healthy patients, gingivitis-UC-sEV were increased compared to the healthy group; while no differences were found in sEV size, oral bacterial gDNA, and DNA methylation for five cytokine gene promoters, for both UC-sEV and SEC-sEV. Overall, the data indicate that SEC results in a higher yield of salivary sEV, with no significant differences in sEV DNA epigenetics, compared to UC. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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17 pages, 2511 KiB

Open AccessArticle

Cells Derived from Human Long Bone Appear More Differentiated and More Actively Stimulate Osteoclastogenesis Compared to Alveolar Bone-Derived Cells

by Cindy Kelder, Cornelis J. Kleverlaan, Marjolijn Gilijamse, Astrid D. Bakker and Teun J. de Vries

Int. J. Mol. Sci. 2020, 21(14), 5072; https://doi.org/10.3390/ijms21145072 - 17 Jul 2020

Cited by 16 | Viewed by 2955

Abstract

Osteoblasts derived from mouse skulls have increased osteoclastogenic potential compared to long bone osteoblasts when stimulated with 1,25(OH)₂ vitamin D₃ (vitD₃). This indicates that bone cells from specific sites can react differently to biochemical signals, e.g., during inflammation or [...] Read more.

Osteoblasts derived from mouse skulls have increased osteoclastogenic potential compared to long bone osteoblasts when stimulated with 1,25(OH)₂ vitamin D₃ (vitD₃). This indicates that bone cells from specific sites can react differently to biochemical signals, e.g., during inflammation or as emitted by bioactive bone tissue-engineering constructs. Given the high turn-over of alveolar bone, we hypothesized that human alveolar bone-derived osteoblasts have an increased osteogenic and osteoclastogenic potential compared to the osteoblasts derived from long bone. The osteogenic and osteoclastogenic capacity of alveolar bone cells and long bone cells were assessed in the presence and absence of osteotropic agent vitD₃. Both cell types were studied in osteogenesis experiments, using an osteogenic medium, and in osteoclastogenesis experiments by co-culturing osteoblasts with peripheral blood mononuclear cells (PBMCs). Both osteogenic and osteoclastic markers were measured. At day 0, long bones seem to have a more late-osteoblastic/preosteocyte-like phenotype compared to the alveolar bone cells as shown by slower proliferation, the higher expression of the matrix molecule Osteopontin (OPN) and the osteocyte-enriched cytoskeletal component Actin alpha 1 (ACTA1). This phenotype was maintained during the osteogenesis assays, where long bone-derived cells still expressed more OPN and ACTA1. Under co-culture conditions with PBMCs, long bone cells also had a higher Tumor necrose factor-alfa (TNF-α) expression and induced the formation of osteoclasts more than alveolar bone cells. Correspondingly, the expression of osteoclast genes dendritic cell specific transmembrane protein (DC-STAMP) and Receptor activator of nuclear factor kappa-Β ligand (RankL) was higher in long bone co-cultures. Together, our results indicate that long bone-derived osteoblasts are more active in bone-remodeling processes, especially in osteoclastogenesis, than alveolar bone-derived cells. This indicates that tissue-engineering solutions need to be specifically designed for the site of application, such as defects in long bones vs. the regeneration of alveolar bone after severe periodontitis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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25 pages, 1083 KiB

Open AccessArticle

Interleukin Gene Variability and Periodontal Bacteria in Patients with Generalized Aggressive Form of Periodontitis

by Petra Borilova Linhartova, Zdenek Danek, Tereza Deissova, Filip Hromcik, Bretislav Lipovy, David Szaraz, Julius Janos, Antonin Fassmann, Jirina Bartova, Ivo Drizhal and Lydie Izakovicova Holla

Int. J. Mol. Sci. 2020, 21(13), 4728; https://doi.org/10.3390/ijms21134728 - 2 Jul 2020

Cited by 17 | Viewed by 3852

Abstract

Host genetic predispositions to dysregulated immune response can influence the development of the aggressive form of periodontitis (AgP) through susceptibility to oral dysbiosis and subsequent host-microbe interaction. This case-control study aimed to perform a multilocus analysis of functional variants in selected interleukin ( [...] Read more.

Host genetic predispositions to dysregulated immune response can influence the development of the aggressive form of periodontitis (AgP) through susceptibility to oral dysbiosis and subsequent host-microbe interaction. This case-control study aimed to perform a multilocus analysis of functional variants in selected interleukin (IL) genes in patients with the generalized form of AgP in a homogenous population. Twelve polymorphisms in IL-1 gene cluster, IL-6 and its receptor, IL-10, IL-17A, and IL-18 were determined in 91 AgP patients and 210 controls. Analysis of seven selected periodontal bacteria in subgingival sulci/pockets was performed with a commercial DNA-microarray kit in a subgroup of 76 individuals. The pilot in vitro study included stimulation of peripheral blood monocytes (PBMC) from 20 individuals with periodontal bacteria and measurement of IL-10 levels using the Luminex method. Only the unctional polymorphism IL-10 −1087 A/G (rs1800896) and specific IL-10 haplotypes were associated with the development of the disease (p < 0.05, P_corr > 0.05). Four bacterial species occurred more frequently in AgP than in controls (p < 0.01, P_corr < 0.05). Elevated IL-10 levels were found in AgP patients, carriers of IL-10 −1087GG genotype, and PBMCs stimulated by periodontal bacteria (p < 0.05, P_corr > 0.05). We therefore conclude that a combination of genetic predisposition to the altered expression of IL-10 and the presence of specific periodontal bacteria may contribute to Th1/Th2 balance disruption and AgP development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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13 pages, 1814 KiB

Open AccessArticle

Role for Lipids Secreted by Irradiated Peripheral Blood Mononuclear Cells in Inflammatory Resolution in Vitro

by Layla Panahipour, Evgeniya Kochergina, Maria Laggner, Matthias Zimmermann, Michael Mildner, Hendrik J. Ankersmit and Reinhard Gruber

Int. J. Mol. Sci. 2020, 21(13), 4694; https://doi.org/10.3390/ijms21134694 - 30 Jun 2020

Cited by 13 | Viewed by 2742

Abstract

Periodontal inflammation is associated with dying cells that potentially release metabolites helping to promote inflammatory resolution. We had shown earlier that the secretome of irradiated, dying peripheral blood mononuclear cells support in vitro angiogenesis. However, the ability of the secretome to promote inflammatory [...] Read more.

Periodontal inflammation is associated with dying cells that potentially release metabolites helping to promote inflammatory resolution. We had shown earlier that the secretome of irradiated, dying peripheral blood mononuclear cells support in vitro angiogenesis. However, the ability of the secretome to promote inflammatory resolution remains unknown. Here, we determined the expression changes of inflammatory cytokines in murine bone marrow macrophages, RAW264.7 cells, and gingival fibroblasts exposed to the secretome obtained from γ-irradiated peripheral blood mononuclear cells in vitro by RT-PCR and immunoassays. Nuclear translocation of p65 was detected by immunofluorescence staining. Phosphorylation of p65 and degradation of IκB was determined by Western blot. The secretome of irradiated peripheral blood mononuclear cells significantly decreased the expression of IL1 and IL6 in primary macrophages and RAW264.7 cells when exposed to LPS or saliva, and of IL1, IL6, and IL8 in gingival fibroblasts when exposed to IL-1β and TNFα. These changes were associated with decreased phosphorylation and nuclear translocation of p65 but not degradation of IκB in macrophages. We also show that the lipid fraction of the secretome lowered the inflammatory response of macrophages exposed to the inflammatory cues. These results demonstrate that the secretome of irradiated peripheral blood mononuclear cells can lower an in vitro simulated inflammatory response, supporting the overall concept that the secretome of dying cells promotes inflammatory resolution. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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16 pages, 2438 KiB

Open AccessArticle

Increase in the Number of Bone Marrow Osteoclast Precursors at Different Skeletal Sites, Particularly in Long Bone and Jaw Marrow in Mice Lacking IL-1RA

by Giuliana Ascone, Yixuan Cao, Ineke D.C. Jansen, Irene Di Ceglie, Martijn H.J. van den Bosch, Arjen B. Blom, Peter L.E.M. van Lent, Vincent Everts and Teun J. de Vries

Int. J. Mol. Sci. 2020, 21(11), 3774; https://doi.org/10.3390/ijms21113774 - 27 May 2020

Cited by 9 | Viewed by 2815

Abstract

Recently, it was shown that interleukin-1β (IL-1β) has diverse stimulatory effects on different murine long bone marrow osteoclast precursors (OCPs) in vitro. In this study, interleukin-1 receptor antagonist deficient (Il1rn^−/−) and wild-type (WT) mice were compared to investigate the effects [...] Read more.

Recently, it was shown that interleukin-1β (IL-1β) has diverse stimulatory effects on different murine long bone marrow osteoclast precursors (OCPs) in vitro. In this study, interleukin-1 receptor antagonist deficient (Il1rn^−/−) and wild-type (WT) mice were compared to investigate the effects of enhanced IL-1 signaling on the composition of OCPs in long bone, calvaria, vertebra, and jaw. Bone marrow cells were isolated from these sites and the percentage of early blast (CD31^hi Ly-6C⁻), myeloid blast (CD31⁺ Ly-6C⁺), and monocyte (CD31⁻ Ly-6C^hi) OCPs was assessed by flow cytometry. At the time-point of cell isolation, Il1rn^−/− mice showed no inflammation or bone destruction yet as determined by histology and microcomputed tomography. However, Il1rn^−/− mice had an approximately two-fold higher percentage of OCPs in long bone and jaw marrow compared to WT. Conversely, vertebrae and calvaria marrow contained a similar composition of OCPs in both strains. Bone marrow cells were cultured with macrophage colony stimulating factor (M-CSF) and receptor of NfκB ligand (RANKL) on bone slices to assess osteoclastogenesis and on calcium phosphate-coated plates to analyze mineral dissolution. Deletion of Il1rn increased osteoclastogenesis from long bone, calvaria, and jaw marrows, and all Il1rn^−/− cultures showed increased mineral dissolution compared to WT. However, osteoclast markers increased exclusively in Il1rn^−/− osteoclasts from long bone and jaw. Collectively, these findings indicate that a lack of IL-1RA increases the numbers of OCPs in vivo, particularly in long bone and jaw, where rheumatoid arthritis and periodontitis develop. Thus, increased bone loss at these sites may be triggered by a larger pool of OCPs due to the disruption of IL-1 inhibitors. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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16 pages, 2805 KiB

Open AccessArticle

Blood Oxidative Stress Modulates Alveolar Bone Loss in Chronically Stressed Rats

by Micaele Maria Lopes Castro, Priscila Cunha Nascimento, Deiweson Souza-Monteiro, Sávio Monteiro Santos, Mayra Barros Arouck, Vinicius Barreto Garcia, Raimundo Fernandes de Araújo, Jr., Aurigena Antunes de Araujo, Gabriela de Souza Balbinot, Fabrício Mezzomo Collares, Cassiano Kuchenbecker Rosing, Marta Chagas Monteiro, Cristiane Socorro Ferraz Maia and Rafael Rodrigues Lima

Int. J. Mol. Sci. 2020, 21(10), 3728; https://doi.org/10.3390/ijms21103728 - 25 May 2020

Cited by 10 | Viewed by 3519

Abstract

We aimed to investigate the effects of chronic stress (CS) on experimental periodontitis (EP) in rats. For this, 28 Wistar rats were divided into four groups: control, ligature-induced experimental periodontitis (EP), chronic stress (CS; by physical restraint model) and CS+EP (association of chronic [...] Read more.

We aimed to investigate the effects of chronic stress (CS) on experimental periodontitis (EP) in rats. For this, 28 Wistar rats were divided into four groups: control, ligature-induced experimental periodontitis (EP), chronic stress (CS; by physical restraint model) and CS+EP (association of chronic stress and ligature-induced periodontitis). The experimental period lasted 30 days, including exposure to CS every day and ligature was performed on the 15th experimental day. After 30 days, the animals were submitted to the behavioral test of the elevated plus maze (EPM). Next, rats were euthanized for blood and mandible collection in order to evaluate the oxidative biochemistry (by nitric oxide (NO), reduced-glutathione activity (GSH), and thiobarbituric acid reactive substance levels (TBARS)) and alveolar bone characterization (by morphometric, micro-CT, and immunohistochemistry), respectively. The behavioral parameters evaluated in EPM indicated higher anxiogenic activity in the CS and CS+EP, groups, which is a behavioral reflex of CS. The results showed that CS was able to change the blood oxidative biochemistry in CS and CS+EP groups, decrease GSH activity in the blood, and increase the NO and TBARS concentrations. Thus, CS induces oxidative blood imbalance, which can potentialize or generate morphological, structural, and metabolic damages to the alveolar bone. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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13 pages, 3756 KiB

Open AccessArticle

Salivary Small Extracellular Vesicles Associated miRNAs in Periodontal Status—A Pilot Study

by Pingping Han, Peter Mark Bartold, Carlos Salomon and Saso Ivanovski

Int. J. Mol. Sci. 2020, 21(8), 2809; https://doi.org/10.3390/ijms21082809 - 17 Apr 2020

Cited by 56 | Viewed by 5231

Abstract

This pilot study aims to investigate whether salivary small extracellular vesicle (sEV)-associated microRNAs could act as potential biomarkers for periodontal disease status. Twenty-nine participants (10 who were healthy, nine with gingivitis, 10 with stage III/IV periodontitis) were recruited and unstimulated whole saliva samples [...] Read more.

This pilot study aims to investigate whether salivary small extracellular vesicle (sEV)-associated microRNAs could act as potential biomarkers for periodontal disease status. Twenty-nine participants (10 who were healthy, nine with gingivitis, 10 with stage III/IV periodontitis) were recruited and unstimulated whole saliva samples were collected. Salivary sEVs were isolated using the size-exclusion chromatography (SEC) method and characterised by morphology, EV-protein and size distribution using transmission electron microscopy (TEM), Western Blot and Nanoparticle Tracking Analysis (NTA), respectively. Ten mature microRNAs (miRNAs) in salivary sEVs and saliva were evaluated using RT-qPCR. The discriminatory power of miRNAs as biomarkers in gingivitis and periodontitis versus healthy controls was evaluated by Receiver Operating Characteristics (ROC) curves. Salivary sEVs were comparable to sEVs morphology, mode, size distribution and particle concentration in healthy, gingivitis and periodontitis patients. Compared to miRNAs in whole saliva, three significantly increased miRNAs (hsa-miR-140-5p, hsa-miR-146a-5p and hsa-miR-628-5p) were only detected in sEVs in periodontitis when compared to that of healthy controls, with a good discriminatory power (area under the curve (AUC) = 0.96) for periodontitis diagnosis. Our study demonstrated that salivary sEVs are a non-invasive source of miRNAs for periodontitis diagnosis. Three miRNAs that are selectively enriched in sEVs, but not whole saliva, could be potential biomarkers for periodontal disease status. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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15 pages, 2039 KiB

Open AccessArticle

Butyrate Decreases ICAM-1 Expression in Human Oral Squamous Cell Carcinoma Cells

by Gabriel Leonardo Magrin, Francesca Di Summa, Franz-Josef Strauss, Layla Panahipour, Michael Mildner, Cesar Augusto Magalhães Benfatti and Reinhard Gruber

Int. J. Mol. Sci. 2020, 21(5), 1679; https://doi.org/10.3390/ijms21051679 - 29 Feb 2020

Cited by 16 | Viewed by 4263

Abstract

Short-chain fatty acids (SCFA) are bacterial metabolites that can be found in periodontal pockets. The expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) within the epithelium pocket is considered to be a key event for the selective transmigration of leucocytes towards [...] Read more.

Short-chain fatty acids (SCFA) are bacterial metabolites that can be found in periodontal pockets. The expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) within the epithelium pocket is considered to be a key event for the selective transmigration of leucocytes towards the gingival sulcus. However, the impact of SCFA on ICAM-1 expression by oral epithelial cells remains unclear. We therefore exposed the oral squamous carcinoma cell line HSC-2, primary oral epithelial cells and human gingival fibroblasts to SCFA, namely acetate, propionate and butyrate, and stimulated with known inducers of ICAM-1 such as interleukin-1-beta (IL1β) and tumor necrosis factor-alfa (TNFα). We report here that butyrate but not acetate or propionate significantly suppressed the cytokine-induced ICAM-1 expression in HSC-2 epithelial cells and primary epithelial cells. The G-protein coupled receptor-43 (GPR43/ FFAR2) agonist but not the histone deacetylase inhibitor, trichostatin A, mimicked the butyrate effects. Butyrate also attenuated the nuclear translocation of p65 into the nucleus on HSC-2 cells. The decrease of ICAM-1 was independent of Nrf2/HO-1 signaling and phosphorylation of JNK and p38. Nevertheless, butyrate could not reverse an ongoing cytokine-induced ICAM-1 expression in HSC-2 cells. Overall, these observations suggest that butyrate can attenuate cytokine-induced ICAM-1 expression in cells with epithelial origin. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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17 pages, 1832 KiB

Open AccessArticle

T Cell Proliferation Is Induced by Chronically TLR2-Stimulated Gingival Fibroblasts or Monocytes

by Carolyn G. J. Moonen, Gerasimos D. Karlis, Ton Schoenmaker, Tim Forouzanfar, Bruno G. Loos and Teun J. de Vries

Int. J. Mol. Sci. 2019, 20(24), 6134; https://doi.org/10.3390/ijms20246134 - 5 Dec 2019

Cited by 12 | Viewed by 4617

Abstract

During inflammation of the gums, resident cells of the periodontium, gingival fibroblasts (GFs), interact with heterogeneous cell populations of the innate and adaptive immune system that play a crucial role in protecting the host from pathogenic infectious agents. We investigated the effects of [...] Read more.

During inflammation of the gums, resident cells of the periodontium, gingival fibroblasts (GFs), interact with heterogeneous cell populations of the innate and adaptive immune system that play a crucial role in protecting the host from pathogenic infectious agents. We investigated the effects of chronic inflammation, by exposing peripheral blood mononuclear cells (PBMCs), peripheral blood lymphocyte (PBL) cultures, and GF–PBMC cocultures to Toll-like receptor 2 (TLR2) and TLR4 activators for 21 days and assessed whether this influenced leukocyte retention, survival, and proliferation. Chronic stimulation of PBMC–GF cocultures with TLR2 and TLR4 agonists induced a reduction of NK (CD56+CD3−), T (CD3+), and B (CD19+) cells, whereas the number of TLR-expressing monocytes were unaffected. TLR2 agonists doubled the T cell proliferation, likely of a selective population, given the net decrease of T cells. Subsequent chronic exposure experiments without GF, using PBMC and PBL cultures, showed a significantly (p < 0.0001) increased proinflammatory cytokine production of TNF-α and IL-1β up to 21 days only in TLR2-activated PBMC with concomitant T cell proliferation, suggesting a role for monocytes. In conclusion, chronic TLR activation mediates the shift in cell populations during infection. Particularly, TLR2 activators play an important role in T cell proliferation and proinflammatory cytokine production by monocytes, suggesting that TLR2 activation represents a bridge between innate and adaptive immunity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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Review

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25 pages, 1336 KiB

Open AccessReview

Oral Microbiota Features in Subjects with Down Syndrome and Periodontal Diseases: A Systematic Review

by Maria Contaldo, Alberta Lucchese, Antonio Romano, Fedora Della Vella, Dario Di Stasio, Rosario Serpico and Massimo Petruzzi

Int. J. Mol. Sci. 2021, 22(17), 9251; https://doi.org/10.3390/ijms22179251 - 26 Aug 2021

Cited by 23 | Viewed by 4351

Abstract

Down syndrome (DS) is a genetic disorder associated with early-onset periodontitis and other periodontal diseases (PDs). The present work aimed to systematically review the scientific literature reporting studies in vivo on oral microbiota features in subjects with DS and related periodontal health and [...] Read more.

Down syndrome (DS) is a genetic disorder associated with early-onset periodontitis and other periodontal diseases (PDs). The present work aimed to systematically review the scientific literature reporting studies in vivo on oral microbiota features in subjects with DS and related periodontal health and to highlight any correlation and difference with subjects not affected by DS, with and without PDs. PubMed, Web of Science, Scopus and Cochrane were searched for relevant studies in May 2021. The participants were subjects affected by Down syndrome (DS) with and without periodontal diseases; the study compared subjects with periodontal diseases but not affected by DS, and DS without periodontal diseases; the outcomes were the differences in oral microbiota/periodontopathogen bacterial composition among subjects considered; the study design was a systematic review. Study quality was assessed with risk of bias in non-randomized studies of interventions (ROBINS-I). Of the 954 references retrieved, 26 studies were considered. The conclusions from the qualitative assessment of the papers revealed an increasing knowledge over the last years of the microbiota associated with DS and their periodontal diseases, in comparison with healthy subjects and subjects with other kinds of mental disabilities. Few data have emerged on the mycobiome and virobiome of DS, hence, further investigations are still necessary. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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46 pages, 761 KiB

Open AccessReview

Application of Ligature-Induced Periodontitis in Mice to Explore the Molecular Mechanism of Periodontal Disease

by Peiya Lin, Hiromi Niimi, Yujin Ohsugi, Yosuke Tsuchiya, Tsuyoshi Shimohira, Keiji Komatsu, Anhao Liu, Takahiko Shiba, Akira Aoki, Takanori Iwata and Sayaka Katagiri

Int. J. Mol. Sci. 2021, 22(16), 8900; https://doi.org/10.3390/ijms22168900 - 18 Aug 2021

Cited by 74 | Viewed by 8687

Abstract

Periodontitis is an inflammatory disease characterized by the destruction of the periodontium. In the last decade, a new murine model of periodontitis has been widely used to simulate alveolar bone resorption and periodontal soft tissue destruction by ligation. Typically, 3-0 to 9-0 silks [...] Read more.

Periodontitis is an inflammatory disease characterized by the destruction of the periodontium. In the last decade, a new murine model of periodontitis has been widely used to simulate alveolar bone resorption and periodontal soft tissue destruction by ligation. Typically, 3-0 to 9-0 silks are selected for ligation around the molars in mice, and significant bone loss and inflammatory infiltration are observed within a week. The ligature-maintained period can vary according to specific aims. We reviewed the findings on the interaction of systemic diseases with periodontitis, periodontal tissue destruction, the immunological and bacteriological responses, and new treatments. In these studies, the activation of osteoclasts, upregulation of pro-inflammatory factors, and excessive immune response have been considered as major factors in periodontal disruption. Multiple genes identified in periodontal tissues partly reflect the complexity of the pathogenesis of periodontitis. The effects of novel treatment methods on periodontitis have also been evaluated in a ligature-induced periodontitis model in mice. This model cannot completely represent all aspects of periodontitis in humans but is considered an effective method for the exploration of its mechanisms. Through this review, we aimed to provide evidence and enlightenment for future studies planning to use this model. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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43 pages, 992 KiB

Open AccessReview

In Vitro Cytological Responses against Laser Photobiomodulation for Periodontal Regeneration

by Yujin Ohsugi, Hiromi Niimi, Tsuyoshi Shimohira, Masahiro Hatasa, Sayaka Katagiri, Akira Aoki and Takanori Iwata

Int. J. Mol. Sci. 2020, 21(23), 9002; https://doi.org/10.3390/ijms21239002 - 26 Nov 2020

Cited by 26 | Viewed by 6616

Abstract

Periodontal disease is a chronic inflammatory disease caused by periodontal bacteria. Recently, periodontal phototherapy, treatment using various types of lasers, has attracted attention. Photobiomodulation, the biological effect of low-power laser irradiation, has been widely studied. Although many types of lasers are applied in [...] Read more.

Periodontal disease is a chronic inflammatory disease caused by periodontal bacteria. Recently, periodontal phototherapy, treatment using various types of lasers, has attracted attention. Photobiomodulation, the biological effect of low-power laser irradiation, has been widely studied. Although many types of lasers are applied in periodontal phototherapy, molecular biological effects of laser irradiation on cells in periodontal tissues are unclear. Here, we have summarized the molecular biological effects of diode, Nd:YAG, Er:YAG, Er,Cr:YSGG, and CO₂ lasers irradiation on cells in periodontal tissues. Photobiomodulation by laser irradiation enhanced cell proliferation and calcification in osteoblasts with altering gene expression. Positive effects were observed in fibroblasts on the proliferation, migration, and secretion of chemokines/cytokines. Laser irradiation suppressed gene expression related to inflammation in osteoblasts, fibroblasts, human periodontal ligament cells (hPDLCs), and endothelial cells. Furthermore, recent studies have revealed that laser irradiation affects cell differentiation in hPDLCs and stem cells. Additionally, some studies have also investigated the effects of laser irradiation on endothelial cells, cementoblasts, epithelial cells, osteoclasts, and osteocytes. The appropriate irradiation power was different for each laser apparatus and targeted cells. Thus, through this review, we tried to shed light on basic research that would ultimately lead to clinical application of periodontal phototherapy in the future. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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21 pages, 1679 KiB

Open AccessReview

Periodontal Disease and Senescent Cells: New Players for an Old Oral Health Problem?

by Ruben Aquino-Martinez, Sundeep Khosla, Joshua N. Farr and David G. Monroe

Int. J. Mol. Sci. 2020, 21(20), 7441; https://doi.org/10.3390/ijms21207441 - 9 Oct 2020

Cited by 29 | Viewed by 3624

Abstract

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. [...] Read more.

The recent identification of senescent cells in periodontal tissues has the potential to provide new insights into the underlying mechanisms of periodontal disease etiology. DNA damage-driven senescence is perhaps one of the most underappreciated delayed consequences of persistent Gram-negative bacterial infection and inflammation. Although the host immune response rapidly protects against bacterial invasion, oxidative stress generated during inflammation can indirectly deteriorate periodontal tissues through the damage to vital cell macromolecules, including DNA. What happens to those healthy cells that reside in this harmful environment? Emerging evidence indicates that cells that survive irreparable genomic damage undergo cellular senescence, a crucial intermediate mechanism connecting DNA damage and the immune response. In this review, we hypothesize that sustained Gram-negative bacterial challenge, chronic inflammation itself, and the constant renewal of damaged tissues create a permissive environment for the abnormal accumulation of senescent cells. Based on emerging data we propose a model in which the dysfunctional presence of senescent cells may aggravate the initial immune reaction against pathogens. Further understanding of the role of senescent cells in periodontal disease pathogenesis may have clinical implications by providing more sophisticated therapeutic strategies to combat tissue destruction. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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37 pages, 413 KiB

Open AccessReview

The Role of DNA Methylation and Histone Modification in Periodontal Disease: A Systematic Review

by Ismael Khouly, Rosalie Salus Braun, Michelle Ordway, Bradley Eric Aouizerat, Iya Ghassib, Lena Larsson and Farah Asa’ad

Int. J. Mol. Sci. 2020, 21(17), 6217; https://doi.org/10.3390/ijms21176217 - 27 Aug 2020

Cited by 18 | Viewed by 3330

Abstract

Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. [...] Read more.

Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. Therefore, the aim of this systematic review is to identify and synthesize the evidence for an association between DNA methylation/histone modification and periodontal disease and its treatment in human adults. A systematic search was independently conducted to identify articles meeting the inclusion criteria. DNA methylation and histone modifications associated with periodontal diseases, gene expression, epigenetic changes after periodontal therapy, and the association between epigenetics and clinical parameters were evaluated. Sixteen studies were identified. All included studies examined DNA modifications in relation to periodontitis, and none of the studies examined histone modifications. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology, was found. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal disease. IL6, IL6R, IFNG, PTGS2, SOCS1, and TNF were identified as candidate genes that have been assessed for DNA methylation in periodontitis. While several included studies found associations between methylation levels and periodontal disease risk, there is insufficient evidence to support or refute an association between DNA methylation and periodontal disease/therapy in human adults. Further research must be conducted to identify reproducible epigenetic markers and determine the extent to which DNA methylation can be applied as a clinical biomarker. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

29 pages, 903 KiB

Open AccessReview

Gingival Crevicular Fluid Peptidome Profiling in Healthy and in Periodontal Diseases

by Mariaimmacolata Preianò, Rocco Savino, Chiara Villella, Corrado Pelaia and Rosa Terracciano

Int. J. Mol. Sci. 2020, 21(15), 5270; https://doi.org/10.3390/ijms21155270 - 24 Jul 2020

Cited by 22 | Viewed by 3910

Abstract

Given its intrinsic nature, gingival crevicular fluid (GCF) is an attractive source for the discovery of novel biomarkers of periodontal diseases. GCF contains antimicrobial peptides and small proteins which could play a role in specific immune-inflammatory responses to guarantee healthy gingival status and [...] Read more.

Given its intrinsic nature, gingival crevicular fluid (GCF) is an attractive source for the discovery of novel biomarkers of periodontal diseases. GCF contains antimicrobial peptides and small proteins which could play a role in specific immune-inflammatory responses to guarantee healthy gingival status and to prevent periodontal diseases. Presently, several proteomics studies have been performed leading to increased coverage of the GCF proteome, however fewer efforts have been done to explore its natural peptides. To fill such gap, this review provides an overview of the mass spectrometric platforms and experimental designs aimed at GCF peptidome profiling, including our own data and experiences gathered from over several years of matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS) based approach in this field. These tools might be useful for capturing snapshots containing diagnostic clinical information on an individual and population scale, which may be used as a specific code not only for the diagnosis of the nature or the stage of the inflammatory process in periodontal disease, but more importantly, for its prognosis, which is still an unmet medical need. As a matter of fact, current peptidomics investigations suffer from a lack of standardized procedures, posing a serious problem for data interpretation. Descriptions of the efforts to address such concerns will be highlighted. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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19 pages, 699 KiB

Open AccessReview

Effects of Short-Chain Fatty Acids on Human Oral Epithelial Cells and the Potential Impact on Periodontal Disease: A Systematic Review of In Vitro Studies

by Gabriel Leonardo Magrin, Franz Josef Strauss, Cesar Augusto Magalhães Benfatti, Lucianne Cople Maia and Reinhard Gruber

Int. J. Mol. Sci. 2020, 21(14), 4895; https://doi.org/10.3390/ijms21144895 - 11 Jul 2020

Cited by 28 | Viewed by 4263

Abstract

Short-chain fatty acids (SCFA), bacterial metabolites released from dental biofilm, are supposed to target the oral epithelium. There is, however, no consensus on how SCFA affect the oral epithelial cells. The objective of the present study was to systematically review the available in [...] Read more.

Short-chain fatty acids (SCFA), bacterial metabolites released from dental biofilm, are supposed to target the oral epithelium. There is, however, no consensus on how SCFA affect the oral epithelial cells. The objective of the present study was to systematically review the available in vitro evidence of the impact of SCFA on human oral epithelial cells in the context of periodontal disease. A comprehensive electronic search using five databases along with a grey literature search was performed. In vitro studies that evaluated the effects of SCFA on human oral epithelial cells were eligible for inclusion. Risk of bias was assessed by the University of Bristol’s tool for assessing risk of bias in cell culture studies. Certainty in cumulative evidence was evaluated using GRADE criteria (grading of recommendations assessment, development, and evaluation). Of 3591 records identified, 10 were eligible for inclusion. A meta-analysis was not possible due to the heterogeneity between the studies. The risk of bias across the studies was considered “serious” due to the presence of methodological biases. Despite these limitations, this review showed that SCFA negatively affect the viability of oral epithelial cells by activating a series of cellular events that includes apoptosis, autophagy, and pyroptosis. SCFA impair the integrity and presumably the transmigration of leucocytes through the epithelial layer by changing junctional and adhesion protein expression, respectively. SCFA also affect the expression of chemokines and cytokines in oral epithelial cells. Future research needs to identify the underlying signaling cascades and to translate the in vitro findings into preclinical models. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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14 pages, 2631 KiB

Open AccessReview

Expression of MicroRNAs in Periodontal and Peri-Implant Diseases: A Systematic Review and Meta-Analysis

by Farah Asa’ad, Carlos Garaicoa-Pazmiño, Christer Dahlin and Lena Larsson

Int. J. Mol. Sci. 2020, 21(11), 4147; https://doi.org/10.3390/ijms21114147 - 10 Jun 2020

Cited by 38 | Viewed by 4976

Abstract

Aim: The purpose of this review was to evaluate the expression patterns of miRNAs in periodontal and peri-implant diseases, while identifying potential miRNAs with the greatest diagnostic ability as an oral fluid biomarker. Materials and methods: Human and animal studies were included when [...] Read more.

Aim: The purpose of this review was to evaluate the expression patterns of miRNAs in periodontal and peri-implant diseases, while identifying potential miRNAs with the greatest diagnostic ability as an oral fluid biomarker. Materials and methods: Human and animal studies were included when evaluating expression of miRNAs between health and different forms/stages of diseases, in which microarray and/or real-time polymerase chain reaction (RT-PCR) was carried out to detect fold changes in gene expression. After full-text analysis, 43 articles were considered for a qualitative assessment, and 16 miRNAs were selected to perform meta-analysis. Results: Based on human studies, results showed an overall upregulation of most of the evaluated miRNAs in periodontitis, with miRNA-142-3p and miRNA-146a being the most conclusive on both microarray and RT-PCR values and potentially serving as diagnostic biomarkers for disease activity. Conversely, miR-155 was the only miRNA revealing a statistically significant difference (SSD) (p < 0.05*) in experimental periodontitis models from RT-PCR values. Scarce scientific evidence is available from peri-implant diseases, however, most explored miRNAs in peri-implantitis were downregulated except for miR-145. Conclusions: Although our results revealed that a distinct differential expression of specific miRNAs can be noted between the state of health and disease, future research remains necessary to explore the functional role of specific miRNAs and their potential as therapeutic targets in periodontal and peri-implant diseases. MeSH Terms: periodontitis, peri-implantitis, epigenomics, microarray analysis, real-time polymerase chain reaction, microRNAs. Clinical relevance: Scientific background: Although most research identified different expression levels of miRNAs in periodontal and peri-implant diseases compared to their counterparts, their actual role in the pathogenesis of these conditions remains unclear. Therefore, we aimed to present a systematic review and meta-analysis on the expression patterns of miRNAs in periodontitis and peri-implantitis, while identifying potential miRNAs with the greatest diagnostic ability as an oral fluid biomarker. Principal findings: In periodontitis-related studies, miRNA-142-3p and miRNA-146a were the most conclusive on both microarray and RT-PCR values. Scarce scientific evidence is available from peri-implant diseases. Practical implications: Both miRNA-142-3p and miRNA-146a might serve as future diagnostic biomarkers for disease activity in periodontitis. Yet, future research remains necessary to explore the functional role of specific miRNAs and their potential as therapeutic targets in periodontal and peri-implant diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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21 pages, 2464 KiB

Open AccessReview

An Evidence-Based Update on the Molecular Mechanisms Underlying Periodontal Diseases

by Syed Saad B. Qasim, Dalal Al-Otaibi, Reham Al-Jasser, Sarhang S. Gul and Muhammad Sohail Zafar

Int. J. Mol. Sci. 2020, 21(11), 3829; https://doi.org/10.3390/ijms21113829 - 28 May 2020

Cited by 27 | Viewed by 10661

Abstract

Several investigators have reported about the intricate molecular mechanism underlying periodontal diseases (PD). Nevertheless, the role of specific genes, cells, or cellular mechanisms involved in the pathogenesis of periodontitis are still unclear. Although periodontitis is one of the most prevalent oral diseases globally, [...] Read more.

Several investigators have reported about the intricate molecular mechanism underlying periodontal diseases (PD). Nevertheless, the role of specific genes, cells, or cellular mechanisms involved in the pathogenesis of periodontitis are still unclear. Although periodontitis is one of the most prevalent oral diseases globally, there are no pre-diagnostic markers or therapeutic targets available for such inflammatory lesions. A pivotal role is played by pro- and anti-inflammatory markers in modulating pathophysiological and physiological processes in repairing damaged tissues. In addition, effects on osteoimmunology is ever evolving due to the ongoing research in understanding the molecular mechanism lying beneath periodontal diseases. The aim of the current review is to deliver an evidence-based update on the molecular mechanism of periodontitis with a particular focus on recent developments. Reports regarding the molecular mechanism of these diseases have revealed unforeseen results indicative of the fact that significant advances have been made to the periodontal medicine over the past decade. There is integrated hypothesis-driven research going on. Although a wide picture of association of periodontal diseases with immune response has been further clarified with present ongoing research, small parts of the puzzle remain a mystery and require further investigations. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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18 pages, 1139 KiB

Open AccessReview

Toll-Like Receptor Signaling and Immune Regulatory Lymphocytes in Periodontal Disease

by Yingzhi Gu and Xiaozhe Han

Int. J. Mol. Sci. 2020, 21(9), 3329; https://doi.org/10.3390/ijms21093329 - 8 May 2020

Cited by 40 | Viewed by 7311

Abstract

Periodontitis is known to be initiated by periodontal microbiota derived from biofilm formation. The microbial dysbiotic changes in the biofilm trigger the host immune and inflammatory responses that can be both beneficial for the protection of the host from infection, and detrimental to [...] Read more.

Periodontitis is known to be initiated by periodontal microbiota derived from biofilm formation. The microbial dysbiotic changes in the biofilm trigger the host immune and inflammatory responses that can be both beneficial for the protection of the host from infection, and detrimental to the host, causing tissue destruction. During this process, recognition of Pathogen-Associated Molecular Patterns (PAMPs) by the host Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs) play an essential role in the host–microbe interaction and the subsequent innate as well as adaptive responses. If persistent, the adverse interaction triggered by the host immune response to the microorganisms associated with periodontal biofilms is a direct cause of periodontal inflammation and bone loss. A large number of T and B lymphocytes are infiltrated in the diseased gingival tissues, which can secrete inflammatory mediators and activate the osteolytic pathways, promoting periodontal inflammation and bone resorption. On the other hand, there is evidence showing that immune regulatory T and B cells are present in the diseased tissue and can be induced for the enhancement of their anti-inflammatory effects. Changes and distribution of the T/B lymphocytes phenotype seem to be a key determinant of the periodontal disease outcome, as the functional activities of these cells not only shape up the overall immune response pattern, but may directly regulate the osteoimmunological balance. Therefore, interventional strategies targeting TLR signaling and immune regulatory T/B cells may be a promising approach to rebalance the immune response and alleviate bone loss in periodontal disease. In this review, we will examine the etiological role of TLR signaling and immune cell osteoclastogenic activity in the pathogenesis of periodontitis. More importantly, the protective effects of immune regulatory lymphocytes, particularly the activation and functional role of IL-10 expressing regulatory B cells, will be discussed. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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14 pages, 2920 KiB

Open AccessReview

Functional Relationship between Osteogenesis and Angiogenesis in Tissue Regeneration

by Francesca Diomede, Guya Diletta Marconi, Luigia Fonticoli, Jacopo Pizzicanella, Ilaria Merciaro, Placido Bramanti, Emanuela Mazzon and Oriana Trubiani

Int. J. Mol. Sci. 2020, 21(9), 3242; https://doi.org/10.3390/ijms21093242 - 3 May 2020

Cited by 266 | Viewed by 9982

Abstract

Bone tissue renewal can be outlined as a complicated mechanism centered on the interaction between osteogenic and angiogenic events capable of leading to bone formation and tissue renovation. The achievement or debacle of bone regeneration is focused on the primary role of vascularization [...] Read more.

Bone tissue renewal can be outlined as a complicated mechanism centered on the interaction between osteogenic and angiogenic events capable of leading to bone formation and tissue renovation. The achievement or debacle of bone regeneration is focused on the primary role of vascularization occurrence; in particular, the turning point is the opportunity to vascularize the bulk scaffolds, in order to deliver enough nutrients, growth factors, minerals and oxygen for tissue restoration. The optimal scaffolds should ensure the development of vascular networks to warrant a positive suitable microenvironment for tissue engineering and renewal. Vascular Endothelial Growth Factor (VEGF), a main player in angiogenesis, is capable of provoking the migration and proliferation of endothelial cells and indirectly stimulating osteogenesis, through the regulation of the osteogenic growth factors released and through paracrine signaling. For this reason, we concentrated our attention on two principal groups involved in the renewal of bone tissue defects: the cells and the scaffold that should guarantee an effective vascularization process. The application of Mesenchymal Stem Cells (MSCs), an excellent cell source for tissue restoration, evidences a crucial role in tissue engineering and bone development strategies. This review aims to provide an overview of the intimate connection between blood vessels and bone formation that appear during bone regeneration when MSCs, their secretome—Extracellular Vesicles (EVs) and microRNAs (miRNAs) —and bone substitutes are used in combination. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Periodontal Disease)

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