FcrRIIA基因多态性与牙周炎关系的研究进展

牙周炎是一种由菌斑引起的以牙周软组织和牙槽骨破坏为特征的慢性感染性疾病,其病因尚不明确,目前普遍认为是细菌 感染和宿主防御相互作用的结果,受遗传有关的宿主易感性、环境、行为因素的影响。致病菌的存在是牙周炎发生的必要条件,基 因因素影响宿主在应对细菌免疫应答过程中的强度,从而导致不同程度的牙周组织破坏。许多有关牙周炎基因方面的研究把目 光对准了在免疫调节和新陈代谢中发挥重要作用的物质的基因多态性,比如细胞因子、细胞表面受体、趋化因子、酶以及其他与 抗原识别有关的物质。FcrR 就是其中之一。FcrR 属于免疫球蛋白超家族,主要有FcrRI、FcrRII、FcrRIII 三类,大量研究表明 FcrRIIA 基因多态性与牙周炎的易感性有关。在针对不同种族的调查中,Fc酌RIIA 基因多态性与牙周炎的易感性的研究结果不尽 相同。也提示我们基因多态性的等位基因频率在各个种族之间存在差异,这种基因标识在界定牙周炎病因和预后方面的相关应 用会变得有所不同。基因诊断将会成为未来牙周病预防和治疗的新方向。本文主要对近年来FcrRIIA 基因多态性与牙周炎关系 的研究进展进行了综述。     

Antisense-mediated inhibition of ICAM-1 expression: a therapeutic strategy against inflammation of human periodontal tissue

Periodontal diseases, such as gingivitis and periodontitis, are caused by a mixed infection by several types of bacteria in the dental plaque, causing a chronic inflammation of the gingival mucosa. Inflammatory processes in conjunction with immune responses to bacterial attacks are generally protective. In profound periodontitis, however, hyperresponsiveness and hypersensitivity of the immune system are counterproductive because of the destruction of the affected periodontal connective tissues. The intercellular adhesion molecule type 1 (ICAM-1) plays a key role in the onset and manifestation of inflammatory responses. Thus, inhibition of ICAM-1 expression could be of therapeutic relevance for the treatment of destructive periodontitis. Here, antisense oligonucleotides (AS-ON) directed against ICAM-1 suppress protein expression and mRNA levels specifically and effectively in primary human endothelial cells of different tissue origin. Moreover, downregulation of ICAM-1 expression is also observed in AS-ON-transfected inflamed gingival mucosal tissue of patients with periodontal diseases. This work strongly suggests exploiting the local topical application of ICAM-1-directed AS-ON as a therapeutic tool against inflammatory processes of the human gingiva.     

Metagenomics: the role of the microbiome in cardiovascular diseases

PURPOSE OF REVIEW: The human oral and intestinal microbiota interact with the host through poorly understood metabolic pathways. Investigation of such complex ecosystems and interactions has been difficult. In this paper, we assess the current evidence supporting the role of the microbiota as a significant determinant of cardiovascular disease risk. RECENT FINDINGS: The link between oral disease and cardiovascular disease was established about 15 years ago. The accumulated evidence supports, but does not prove a causal association between periodontal infection and cardiovascular disease and suggests some physiologically obvious connections between these pathologies, namely, inflammatory and immune responses, and hemostasis. Moreover, some studies have observed higher concentrations of total and LDL-cholesterol and triglycerides and lower concentrations of HDL-cholesterol in individuals with periodontitis before periodontal treatment. Likewise, recent reports suggest the influence of the gut microbiome in the risk of common age-related diseases such as cancer and potentially cardiovascular disease through modification of classical risk factors such as obesity, insulin resistance and plasma lipids. SUMMARY: The recognition that microorganisms may play an even more important role in maintaining human health than in generating diseases places metagenomics as one of the most relevant areas of future research. The knowledge of the hundreds of genomes that we host and their interaction with our own genome shall provide a much more complete understanding of the individual nutritional needs and may be an obligated part of future personalized healthcare approaches.     

Rheumatoid arthritis and periodontitis; a possible link via citrullination

Rheumatoid Arthritis (RA) and chronic and aggressive periodontitis are chronic inflammatory disorders characterized by deregulation of the host inflammatory response. Increased secretion of pro-inflammatory mediators results in soft and hard tissue destruction of the synovium and periodontium respectively. Both diseases share risk factors and have pathological pathways in common, resulting in loss of function and disability as a final clinical outcome. This article discusses possible interactions, particularly related to the periodontal pathogen Porphyromonas gingivalis, which could explain the observed association between these two prevalent diseases.     

Increased local matrix metalloproteinase-8 expression in the periodontal connective tissues of smokers with periodontal disease

Matrix metalloproteinase (MMP)-8 has been associated with the progression of periodontitis, a common inflammatory disease of the supporting structures of the teeth, and with other degradative diseases. Tobacco smokers are at high risk of developing periodontitis that may progress more rapidly and respond poorly to treatment. Therefore, MMP-8 expression was determined by immunofluorescence staining in 60 random, computer-selected fields in the excised periodontal tissues of smokers and non-smokers, balanced for age, gender, and periodontal status. Immunofluorescence intensity, representing MMP-8 expression, in the periodontal tissues of smokers (30 fields from 6 subjects, mean 1154+/-124 units) was significantly higher than that in the periodontal tissues of non-smokers (30 fields from 6 subjects, mean 817+/-60 units; p < 0.05). Serum MMP-8 concentrations were measured by ELISA and compared in a larger group of smokers (n = 20) and age- and gender-balanced non-smokers (n = 20). Systemic MMP-8 concentrations in smokers and non-smokers were not significantly different (p > 0.05). A local tobacco-related increase in MMP-8 burden may contribute to periodontal disease progression in tobacco smokers. This finding may also have relevance to other tobacco-induced inflammatory diseases, such as vascular and pulmonary diseases.     

Single nucleotide polymorphisms associated with aggressive periodontitis and severe chronic periodontitis in Japanese

Periodontitis is a common inflammatory disease causing destruction of periodontal tissues. It is a multifactor disease involving genetic factors and oral environmental factors. To determine genetic risk factors associated with aggressive periodontitis or severe chronic periodontitis, single nucleotide polymorphisms (SNPs) in multiple candidate genes were investigated in Japanese. We studied 134 patients with aggressive periodontitis, 117 patients with severe chronic periodontitis, and 125 healthy volunteers without periodontitis, under case-control setting, and 310 SNPs in 125 candidate genes were genotyped. Association evaluation by Fisher's exact test (p < 0.01) revealed statistically significant SNPs in multiple genes, not only in inflammatory mediators (IL6ST and PTGDS, associated with aggressive periodontitis; and CTSD, associated with severe chronic periodontitis), but also in structural factors of periodontal tissues (COL4A1, COL1A1, and KRT23, associated with aggressive periodontitis; and HSPG2, COL17A1, and EGF, associated with severe chronic periodontitis). These appear to be good candidates as genetic factors for future study.     

Regeneration of bone and periodontal ligament induced by recombinant amelogenin after periodontitis

Regeneration of mineralized tissues affected by chronic diseases comprises a major scientific and clinical challenge. Periodontitis, one such prevalent disease, involves destruction of the tooth-supporting tissues, alveolar bone, periodontal-ligament and cementum, often leading to tooth loss. In 1997, it became clear that, in addition to their function in enamel formation, the hydrophobic ectodermal enamel matrix proteins (EMPs) play a role in the regeneration of these periodontal tissues. The epithelial EMPs are a heterogeneous mixture of polypeptides encoded by several genes. It was not clear, however, which of these many EMPs induces the regeneration and what mechanisms are involved. Here we show that a single recombinant human amelogenin protein (rHAM⁺), induced in vivo regeneration of all tooth-supporting tissues after creation of experimental periodontitis in a dog model. To further understand the regeneration process, amelogenin expression was detected in normal and regenerating cells of the alveolar bone (osteocytes, osteoblasts and osteoclasts), periodontal ligament, cementum and in bone marrow stromal cells. Amelogenin expression was highest in areas of high bone turnover and activity. Further studies showed that during the first 2 weeks after application, rHAM⁺ induced, directly or indirectly, significant recruitment of mesenchymal progenitor cells, which later differentiated to form the regenerated periodontal tissues. The ability of a single protein to bring about regeneration of all periodontal tissues, in the correct spatio-temporal order, through recruitment of mesenchymal progenitor cells, could pave the way for development of new therapeutic devices for treatment of periodontal, bone and ligament diseases based on rHAM⁺.     

Signaling pathways involved in the regulation of TNFα-induced toll-like receptor 2 expression in human gingival fibroblasts

Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFα-induced TLR2 expression. Our results showed that TNFα increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) were involved in the regulation of TNFα-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFα. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.     

Haplotypes in the Interleukin 8 Gene and Their Association with Chronic Periodontitis Susceptibility

Interleukin-8 (IL-8), which is responsible for the migration and activation of neutrophils, is an important inflammatory mediator involved in the initiation and amplification of acute inflammatory reactions and chronic inflammatory processes. IL-8 plays an important role in periodontitis, an inflammatory disease characterized by the loss of connective tissue and alveolar bone. The aim of this study was to investigate whether the SNPs rs2227307 (+396) and rs2227306 (+781), and the haplotypes they formed together with the previously investigated rs4073 (-251), were associated with chronic periodontitis susceptibility. Clinical periodontal exams were performed and DNA samples were collected from 493 individuals (223 with periodontitis and 270 controls). Associations between SNPs, haplotypes, and subject phenotypes were analyzed using the χ(2) test followed by multivariate logistic regression modeling. We conclude that the +396TT genotype and the haplotypes ATC/TTC and AGT/TGC were significantly associated with chronic periodontitis susceptibility in Brazilians.     

Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice

Inflammatory periodontal diseases constitute one of the most common infections in humans, resulting in the destruction of the supporting structures of the dentition. Circulating neutrophils are an essential component of the human innate immune system. We observed that mice deficient for the major lysosomal-associated membrane protein-2 (LAMP-2) developed severe periodontitis early in life. This development was accompanied by a massive accumulation of bacterial plaque along the tooth surfaces, gingival inflammation, alveolar bone resorption, loss of connective tissue fiber attachment, apical migration of junctional epithelium, and pathological movement of the molars. The inflammatory lesions were dominated by polymorphonuclear leukocytes (PMNs) apparently being unable to efficiently clear bacterial pathogens. Systemic treatment of LAMP-2-deficient mice with antibiotics prevented the periodontal pathology. Isolated PMNs from LAMP-2-deficient mice showed an accumulation of autophagic vacuoles and a reduced bacterial killing capacity. Oxidative burst response was not altered in these cells. Latex bead and bacterial feeding experiments showed a reduced ability of the phagosomes to acquire an acidic pH and late endocytic markers, suggesting an impaired fusion of late endosomes-lysosomes with phagosomes. This study underlines the importance of LAMP-2 for the maturation of phagosomes in PMNs. It also underscores the requirement of lysosomal fusion events to provide sufficient antimicrobial activity in PMNs, which is needed to prevent periodontal disease.     

实验性牙周炎合并咬合创伤模型的研究进展

不正常的咬合接触关系或者过大的咬合力,造成咀嚼系统各部位的病理性损害或者适应性变化称为咬合创伤,而牙周炎是一种慢性炎症性疾病,是由牙菌斑生物膜引起的牙周组织的感染性疾病,导致牙周支持组织的破坏-牙周袋形成和炎症、进行性的附着丧失和牙槽骨吸收。近年来有学者对咬合创伤作为一类独立疾病进行研究,也有学者将咬合创伤作为牙周炎的一个重要的局部促进因素进行研究。牙周炎和咬合创伤的关系至今不是很明确,关于咬合创伤和牙周炎的相互关系,虽然早在20世纪初已开始研究,却直到70年代才有严格对照的动物实验研究。大鼠牙周炎合并咬合创伤的模型在牙周炎和咬合创伤关系的相关研究中起着十分重要的作用。本文从牙周炎和咬合创伤复合模型的建立方面,综述了各种建模方法的研究进展,以期为牙周炎合并咬合创伤的深入研究提供参考。     

Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines

Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-κΒ pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.     

Arginine-specific gingipains from Porphyromonas gingivalis stimulate production of hepatocyte growth factor (scatter factor) through protease-activated receptors in human gingival fibroblasts in culture

Cystein proteinases (gingipains) from Porphyromonas gingivalis cleave a broad range of in-host proteins and are considered to be key virulence factors in the onset and development of adult periodontitis and host defense evasion. In periodontitis, an inflammatory disease triggered by bacterial infection, the production of hepatocyte growth factor (HGF) is induced not only by various factors derived from the host, such as inflammatory cytokines, but also by bacterial components. In this study we examined the possible enhanced production of HGF produced by human gingival fibroblasts upon stimulation with gingipains. Arginine-specific gingipain (Rgp) caused a marked production of HGF into the supernatant, the induction of HGF expression on the cell surface, and the up-regulation of HGF mRNA expression in a dose-dependent and an enzymatic activity-dependent manner. Because it has been reported that Rgp activated protease-activated receptors (PARs), we examined whether the induction of HGF triggered by Rgps on human gingival fibroblasts occurred through PARs. An RNA interference assay targeted to PAR-1 and PAR-2 mRNA revealed that gingipains-induced secretion of HGF was significantly inhibited by RNA interference targeted to PAR-1 and PAR-2. In addition, the Rgps-mediated HGF induction was completely inhibited by the inhibition of phospholipase C and was clearly inhibited by RNA interference targeted to p65, which is an NF-kappaB component. These results suggest that Rgps activated human gingival fibroblasts to secrete HGF in the inflamed sites and the mechanism(s) involved may actively participate in both inflammatory and reparative processes in periodontal diseases.     

Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.     

Analysis of histone deacetylase inhibitor-induced responses in human periodontal ligament fibroblasts

Periodontal ligament (PDL) fibroblasts play critical roles in the regeneration of periodontal tissues damaged by periodontitis. Histone deacetylase inhibitors (HDIs) have been suggested to be potential tools in tissue engineering. The feasibility of using the HDI, sodium butyrate (NaB) for periodontal regeneration was examined by evaluating its effect on the osteogenic differentiation of human PDL fibroblasts and its modulation of the inflammatory responses to lipopolysaccharide (LPS). NaB did not cause significant cell death at 100 μM but promoted the expression of the osteoblast phenotype (Runx2, osterix, osteocalcin, and bone sialoprotein). NaB significantly inhibited the LPS-induced production of reactive oxygen species and the expression of pro-inflammatory cytokines (IL-1β and TNF-α). These results suggest that HDIs can offer a potential therapeutic agent for periodontal regeneration.     

Associations between marginal periodontitis and rheumatoid arthritis

Chronic destructive periodontitis is no longer considered to be just a local inflammatory process afflicting the periodontal tissues, but a systemic infection. Bacteria, their products and various pro-inflammatory cells and substances can penetrate into the blood stream and infect distant organs and structures. Periodontitis and rheumatoid arthritis indicate several common histo-pathological correlations, as the destroyed osseous tissues and cartilages are permanently washed with inflammatory fluid full of proteolytic and osteolytic substances. Although exact causal and molecular associations between both diseases have not been explained yet, there are some common etiopathogenic correlations that can have influence on relationship between both diseases. Among these factors belong: a positive finding of common genes, genetic polymorphisms and hyper-inflammatory types of some immune competent cells and molecules, common cytokine profiles and increased concentrations of pro-inflammatory mediators in periodontal and joint structures. Periodontitis and some periodontal pathogens can influence various auto-immune reactions connected with rheumatoid arthritis (RF, anti-CCP). Possible causal associations are indicated in some studies dealing with treatment of RA, when a beneficiary effect of RA treatment led to improvement of some periodontal parameters. This relationship works both ways; the periodontal therapy had positive influence on some markers of rheumatoid arthritis. This provides sufficient theoretic evidence to perform professional and personal oral hygiene in a more active way.     

Berberine as a promising natural compound for the treatment of periodontal disease: A focus on anti-inflammatory properties

Accumulating evidence during the last two decades has addressed the potential anti-inflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. Periodontitis is one of the most common chronic and serious inflammatory diseases, in which uncontrolled and unabated host immune responses against periodontopathic pathogens play critical and crucial roles in the disease pathogenesis. Hence, regulating inflammatory responses in periodontitis has a valuable approach and holds promise in treating periodontitis. For the first time, this paper reviews the evidence from in vitro and in vivo experimental models to explore the anti-inflammatory effects of BBR in periodontitis and exhibits that BBR has the high potency to exert anti-inflammatory effects by reducing expression and secretion of pro-inflammatory mediators including TNF-α, IL-1β, IL-17, RANKL, MMP-2, MMP-9 and MCP-1. The BBR-mediated anti-inflammatory actions could translate into the inhibition of the periodontal tissues and alveolar bone destruction and the control of the disease in vivo. As the second aim of this paper, we also paid attention to the therapeutic potential of BBR in treating human diseases regarding its anti-inflammatory properties.     

Periodontal infections and atherosclerosis: mere associations?

PURPOSE OF REVIEW: Several lines of evidence from the last few decades suggest that periodontitis is an important risk factor for cardiovascular diseases. In this review we discuss the recent findings on the systemic effects of periodontitis, which may contribute to the pathogenesis of atherosclerosis, with a special emphasis on lipoproteins. RECENT FINDINGS: In addition to the epidemiological studies exploring the direct or indirect relationship between clinical periodontitis and cardiovascular diseases, studies utilizing serology, animal models, cell cultures, and biochemistry of lipoproteins have been published. Local infection in the periodontal pockets triggers a systemic inflammatory response releasing inflammatory mediators and awakens a strong immune response against periodontal pathogens. Elevated systemic antibody levels especially to Porphyromonas gingivalis are associated with an increased risk for atherosclerosis. Periodontitis is also accompanied by proatherogenic changes in both low and high density lipoproteins, which lead to enhanced cholesteryl ester uptake by and reduced cholesterol efflux from macrophages. Vesicles and lipopolysaccharide isolated from P. gingivalis activate macrophages to convert into foam cells. Moreover, animal studies have demonstrated that infection by P. gingivalis enhances progression of atherosclerosis. SUMMARY: Recent studies have clarified the mechanisms by which periodontitis may contribute to the development of atherosclerosis. Serological, animal, and cell culture studies provide evidence that infection by P. gingivalis may promote atherosclerosis. The influence of periodontitis on lipoprotein metabolism has emerged as a new, important factor. Recent studies provide experimental proof that periodontitis may predispose to atherosclerosis.