Mastication inefficiency due to diminished or lack of occlusal support is associated with increased blood glucose levels in patients with type 2 diabetes.

BACKGROUND: It has been shown that mastication may contribute to a lower risk of diabetes, and occlusal support reduced the risk of diabetes by improving glucose metabolism after meals. However, the relationship between inefficient mastication and blood glucose levels in patients with type 2 diabetes (T2D) remains unclear. This retrospective study, therefore, aimed to investigate the association between mastication inefficiency due to diminished occlusal support and blood glucose control in subjects with T2D. METHODS: Ninety-four subjects (mean of 54.9 years) were recruited in this study. Subjects with at least 1-year T2D medical history and current medications for T2D were included. Subjects were divided into 2 groups: The control group (41 subjects) included Eichner group A (4 occlusal functional areas in the posterior area). The test group (53 subjects) included Eichner group B (1-3 occlusal functional areas) and group C (no natural occlusal contact). Blood glucose level was significantly lower in the control group participants than in the test group. Subject(s) showing diminished or lack of occlusal support and requiring a fixed restoration were treated with an implant-supported fixed restoration. These groups' levels of glycated hemoglobin (A1c) were compared using the independent student t-test. RESULTS: Blood glucose level was significantly lower in the control group (7.48) as compared to those in the test group (9.42). The mean differences between the two groups were 1.94 ± 0.39 (p = 0.0001). Differences in white blood cell counts and body mass index (BMI) were not statistically significant between groups. Blood glucose levels could be reduced (from A1c 9.1 to 6.2) following a fixed implant-supported restoration in T2D patients with diminished occlusal support. CONCLUSION: The results suggested that masticatory inefficiency due to diminished dental occlusion was associated with an increase in poor controlled-blood glucose levels among T2D patients.

The effect of membrane exposure on lateral ridge augmentation: a case-controlled study.

BACKGROUND: The effect of membrane exposure on guided bone regeneration (GBR) for lateral ridge augmentation has been poorly addressed. This case-controlled study aimed to investigate potential effect of membrane exposure lateral ridge augmentation and subsequent implant placement. METHODS: A total of 14 patients that did receive lateral ridge augmentation procedure using allogeneic cancellous graft particulate in combination with an alloplastic bioresorbable matrix barrier were retrospectively selected for this study. Bone width was measured at the crest with a digital caliper before bone augmentation and at the reopening for implant placement 4 months later for all patients. Cases where primary flap closure was achieved and the barrier did not expose throughout the time until implant placement were assigned to the control group (n = 7). Cases where primary closure could not be achieved or a barrier exposure happened within the first week following the initial surgery were assigned to the test group. RESULTS: The measured alveolar ridge width before surgery as well as after GBR procedure were not statistically significant different between the two groups (p > 0.05). Both groups showed a significant (p < 0.05) increase in their mean alveolar ridge width 4 months after later augmentation procedure, from 3.4 ± 1.2 to 6.0 ± 1.1 mm in the control group and from 3.6 ± 1.0 to 5.0 ± 1.4 mm in the test group. However, the mean alveolar ridge gain was significantly greater in the control group than in the test group (p < 0.05). Consequently, the reduction of the augmented alveolar ridge was significantly higher in the test group averaging to 4.7 mm than for the control group showing a loss of 3.1 mm after 4 months, respectively. However, in all 14 cases, successful implant placement was achieved after 4 months. CONCLUSIONS: Within the limit of this study, it can be concluded that early exposure of a bioresorbable matrix barrier during lateral ridge augmentation may compromise the results of the GBR procedure but may still result in a favorable alveolar ridge width gain that allows for the placement of dental implants.

Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss.

Leukocyte adhesion deficiency type I (LAD-I), a disease syndrome associated with frequent microbial infections, is caused by mutations on the CD18 subunit of ß2 integrins. LAD-I is invariably associated with severe periodontal bone loss, which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection. We provide an alternative mechanism by showing that the cytokine interleukin-17 (IL-17) plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice--which exhibit the LAD-I periodontal phenotype--was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue, although innate lymphoid cells also contributed to pathological IL-17 elevation in the LFA-1-deficient mice. Local treatment with antibodies to IL-17 or IL-23 in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Therefore, our findings support an IL-17-targeted therapy for periodontitis in LAD-I patients.

The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss.

Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.

Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement.

Porphyromonas gingivalis is a low-abundance oral anaerobic bacterium implicated in periodontitis, a polymicrobial inflammatory disease, and the associated systemic conditions. However, the mechanism by which P. gingivalis contributes to inflammation and disease has remained elusive. Here we show that P. gingivalis, at very low colonization levels, triggers changes to the amount and composition of the oral commensal microbiota leading to inflammatory periodontal bone loss. The commensal microbiota and complement were both required for P. gingivalis-induced bone loss, as germ-free mice or conventionally raised C3a and C5a receptor-deficient mice did not develop bone loss after inoculation with P. gingivalis. These findings demonstrate that a single, low-abundance species can disrupt host-microbial homeostasis to cause inflammatory disease. The identification and targeting of similar low-abundance pathogens with community-wide impact may be important for treating inflammatory diseases of polymicrobial etiology.

Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes.

Mammalian biological processes such as inflammation, involve regulation of hundreds of genes controlling onset and termination. MicroRNAs (miRNAs) can translationally repress target mRNAs and regulate innate immune responses. Our model system comprised primary human keratinocytes, which exhibited robust differences in inflammatory cytokine production (interleukin-6 and tumor necrosis factor-alpha) following specific Toll-like receptor 2 and 4 (TLR-2/TLR-4) agonist challenge. We challenged these primary cells with Porphyromonas gingivalis (a Gram-negative bacterium that triggers TLR-2 and TLR-4) and performed miRNA expression profiling. We identified miRNA (miR)-105 as a modulator of TLR-2 protein translation in human gingival keratinocytes. There was a strong inverse correlation between cells that had high cytokine responses following TLR-2 agonist challenge and miR-105 levels. Knock-in and knock-down of miR-105 confirmed this inverse relationship. In silico analysis predicted that miR-105 had complementarity for TLR-2 mRNA, and the luciferase reporter assay verified this. Further understanding of the role of miRNA in host responses may elucidate disease susceptibility and suggest new anti-inflammatory therapeutics.

TLR4 and S1P receptors cooperate to enhance inflammatory cytokine production in human gingival epithelial cells.

Toll-like receptors (TLR) are pattern recognition receptors for highly conserved microbial molecular patterns. Activation of TLR is a pivotal step in the initiation of innate, inflammatory, and immune defense mechanisms. Recent findings indicate that G protein-coupled receptors (GPCR) may modulate TLR signaling, but it is unclear which GPCR are involved in this process. One such cooperation between GPCR and TLR can be attributed to the sphingosine 1-phosphate (S1P) receptor family. The S1P receptors (S1P1-5) are a family of GPCR with a high affinity for S1P, a serum-borne bioactive lipid associated with diverse biological activities such as inflammation and healing. In this study, we show that pro-inflammatory cytokine production, including IL-6 and IL-8, was increased with LPS and concomitant S1P stimulation. Furthermore, elevated cytokine production following LPS and S1P challenge in human gingival epithelial cells (HGEC) was significantly reduced when TLR4, S1P1 or S1P3 signaling was blocked. Our study also shows that S1P1 and S1P3 expression was induced by LPS in HGEC, and this elevated expression enhanced the influence of S1P in its cooperation with TLR4 to increase cytokine production. This cooperation between TLR4 and S1P1 or S1P3 demonstrates that TLR4 and GPCR can interact to enhance cytokine production in epithelial cells.

Interleukin-1beta modulates proinflammatory cytokine production in human epithelial cells.

Periodontitis is a chronic human inflammatory disease initiated and sustained by dental plaque microorganisms. A major contributing pathogen is Porphyromonas gingivalis, a gram-negative bacterium recognized by Toll-like receptor 2 (TLR2) and TLR4, which are expressed by human gingival epithelial cells (HGECs). However, it is still unclear how these cells respond to P. gingivalis and initiate inflammatory and immune responses. We have reported previously that HGECs produce a wide range of proinflammatory cytokines, including interleukin-6 (IL-6), IL-8, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha (TNF-alpha), and IL-1beta. In this study, we show that IL-1beta has a special role in the modulation of other inflammatory cytokines in HGECs challenged with P. gingivalis. Our results show that the increased production of IL-1beta correlates with the cell surface expression of TLR4, and more specifically, TLR4-normal HGECs produce fourfold more IL-1beta than do TLR4-deficient HGECs after challenge. Moreover, blocking the IL-1beta receptor greatly reduces the production of "secondary" proinflammatory cytokines such as IL-8 or IL-6. Our data indicate that the induction of IL-1beta plays an important role in mediating the release of other proinflammatory cytokines from primary human epithelial cells following challenge with P. gingivalis, and this process may be an inflammatory enhancement mechanism adopted by epithelial cells.

Sphingosine 1-phosphate 1 and TLR4 mediate IFN-beta expression in human gingival epithelial cells.

IFN-beta production is a critical step in human innate immune responses and is primarily controlled at the transcription level by highly ordered mechanisms. IFN-beta can be induced by pattern-recognition receptors such as the TLR4. S1P1 is a G protein-coupled receptor, which has a high affinity for sphingosine 1-phosphate (S1P). Although many of the receptors and signaling pathways leading to the expression of IFN-beta have been identified and characterized, it is still unclear how IFN-beta is regulated in primary human gingival epithelial cells (HGECs). In this study, we demonstrate that S1P1 and TLR4, acting in unison, play an important role in IFN-beta expression at the protein and mRNA level in HGECs. We demonstrate that the expression of both IFN-beta and IFN-inducible protein-10 (CXCL-10) is significantly up-regulated by LPS and S1P or LPS and a specific S1P1 agonist. This enhanced innate immune response is attenuated in HGECs by small interfering RNA knockdown of either TLR4 or S1P1. Moreover, we show that triggering of TLR4 results in the increased expression of S1P1 receptors. Furthermore, we found that IFN-regulatory factor 3 activation was maximized by LPS and S1P through PI3K. Our data show that triggering TLR4 increases S1P1, such that both TLR4 and S1P1 acting through PI3K enhancement of IFN-regulatory factor 3 activation increase IFN-beta expression in epithelial cells. The functional association between TLR4 and the S1P1 receptor demonstrates a novel mechanism in the regulation of IFN-beta and CXCL-10 in human primary gingival epithelial cells.

Differential activation of human gingival epithelial cells and monocytes by Porphyromonas gingivalis fimbriae.

Humans develop periodontitis in response to challenge by microbial dental plaque. Inflammation begins after perturbation of gingival epithelial cells by subgingival bacteria interacting through pattern-recognition receptors, including the Toll-like receptors (TLR). Porphyromonas gingivalis is a major periodontopathogen that interacts with epithelial cells through its cell surface fimbriae (FimA), leading to colonization and/or invasion. Previous work by our group has established membrane CD14 as an essential coreceptor for TLR2-mediated activation of transfected cell lines by P. gingivalis FimA. We have shown that gingival epithelial cells express TLR2 but not CD14 on their cell surfaces. We thus speculated that P. gingivalis FimA does not readily activate epithelial innate immune responses but rather functions to promote P. gingivalis colonization in the absence of a vigorous FimA-induced response. This hypothesis was verified by the findings that primary human gingival epithelial cells responded poorly to FimA in terms of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha responses, in stark contrast to the marked response to other TLR2 agonists (Pam3Cys, FSL-1) that are not strictly dependent on CD14. On the other hand, CD14-expressing human primary monocytes responded with high levels of the same cytokines to both FimA and the control TLR2 agonists. The gingival epithelial cells failed to respond to FimA even in the presence of exogenously added soluble CD14. These data indicate that the gingival epithelial cell hyporesponsiveness to FimA is attributable to the lack of membrane-expressed but not soluble CD14. In conclusion, P. gingivalis FimA differentially activates human monocytes and epithelial cells, perhaps reflecting different tactics used by P. gingivalis when interacting with different host cell types or a host strategy to limit inflammation.