Osteoclasts are primary bone-resorbing cells that play a critical role in bone remodeling. Two proteins crucial for osteoclast development are the receptor activator of NF-κB (RANK) and its ligand RANKL. Beside the RANKL/RANK system, other costimulatory signals, such as receptors with multiple immunoglobulin-like domains that are associated with tyrosine-based adapter motifs, are also involved in regulating osteoclast differentiation. We have recently found using genome-wide screening techniques that Notch family molecules are upregulated during RANKL-induced osteoclastogenesis, suggesting that Notch modulates signaling downstream of RANK. Although multiple lines of evidence indicate that Notch signaling dysfunction results in bone disease, the specific involvement for Notch in regulating osteoclastogenesis is still controversial. In this review, we introduce new findings about the role of Notch signaling in osteoclast differentiation, based on the results of other groups and our recent work.

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Mammalian dentition is characterized by regional differentiation into incisors, canines, premolars and molars in each jaw quadrant (heterodonty), and tooth replacement once during the lifetime (diphyodonty). Despite their significance in various research fields, little is known about the developmental mechanisms regulating tooth type (class) determination and diphyodont tooth replacement. The mouse, the most popular laboratory animal, is not appropriate for the investigation of heterodonty and diphyodonty, because of its highly specialized dentition. The house shrew, Suncus murinus, has been suggested to be a potentially excellent model organism to study the mammalian basal condition of tooth development. Using three-dimensional (3-D) reconstructions of dental epithelium from serial histological sections, and Sonic hedgehog (Shh) expression patterns, we have precisely located the tooth-forming regions of all tooth types in the developing jaws of the house shrew. The incisor region in the upper jaw is found to extend across the boundary between the frontonasal and maxillary processes. The molar-forming region is later added distal to the first demarcated tooth-forming regions by secondary extension of the dental lamina. Furthermore, we have elucidated the replacement pattern of the deciduous dentition by succession and addition (accession) of the permanent teeth in the house shrew. On the basis of new knowledge on tooth development in the house shrew, we discuss the developmental mechanisms regulating tooth type determination and diphyodont tooth replacement, and consider future prospects in the field.

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There has been extensive bacteriological research into oral biofilm. Most of these studies examined the bacterial composition of oral biofilm and the bacterial species specific to oral diseases. It is thought that the various metabolites, intracellular metabolic intermediates and end-products produced by metabolic activities of oral biofilm directly relate to oral diseases, such as dental caries and periodontitis. However, the metabolic properties, including functional metabolic pathways and their metabolic regulations, have not been clarified sufficiently because the comprehensive identification and quantification of metabolites, that is, metabolomics (or metabolome analysis) are technically difficult. Recently, a new device consisting of capillary electrophoresis (CE) and a time-of-flight mass spectrometer (TOFMS) has been developed, facilitating the metabolomic investigation of sugar metabolism in oral biofilm. The results clearly showed that oral biofilm metabolomics is possible even with a very small sample, and that almost all metabolites in the central carbon metabolic pathways, the EMP pathway, the pentose-phosphate pathway, and the TCA cycle are present in the oral biofilm in vivo. Metabolomics using CE-TOFMS may offer a new frame of knowledge to answer the question “What are bacteria doing in oral biofilm?” from a metabolic perspective, and possibly provide insight into the relationship between the metabolic properties of oral biofilm and the etiology of oral disease, as well as the influences of medicines, such as fluoride, or a sugar substitute, such as xylitol, on metabolism of the oral biofilm.

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Quorum sensing is a cell-density effect and the regulation of gene expression in response to extracellular chemical signals (quorum-sensing molecules) produced by microorganisms. Hyphal induction in Candid albicans is inhibited by high cell density and also by farnesol, which is a quorum-sensing molecule of the organism. Here, we describe models of the regulation of dimorphism in Candida albicans by farnesol from the latest published data and gene regulation during the initial stages of quorum sensing, which was obtained through microarray analysis.

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Oral biofilms cause various oral infectious diseases, such as periodontitis and dental caries. Asaccharolytic anaerobic Gram-positive rods (AAGPRs) and periodontopathic bacteria, such as Porphyromonas gingivalis, are frequently components of subgingival biofilms. However, AAGPRs are not easy to study, because they are difficult to culture and produce few metabolic products ; thus, the contributions of AAGPRs to periodontitis have yet to be determined. Herein, we describe the growth and formation of AAGPR biofilms and the effect of AAGPRs on the induction of cytokines from human gingival fibroblasts stimulated with periodontopathic bacteria. We also discuss the role of AAGPRs in the progression of periodontitis. Finally, we suggest future avenues of research that will be vital for improving our understanding of the mechanisms by which periodontal disease progresses.

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The development of dental caries has been an important topic in oral microbiology research for several decades. One of the common strains of bacteria oral Streptococcus mutans, has long been considered the primary bacterium involved in the initiation and progression of dental caries. One of the primary virulence traits of S. mutans is sucrose-dependent biofilm formation. However, beginning in the 1970s, several researchers have observed a naturally derived variant of S. mutans defective in biofilm formation, and there have since been numerous studies on this variant. The mechanism of the appearance of this variant has been well established, but little is known about its ecological significance. Additional studies will be needed to advance our understanding of the role and behavior of this colony variant within the oral cavity. In this review, we summarize the development and characterization of this naturally derived variant, and discuss its ecological implications in the oral habitat.

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Biofilm is a colony-like aggregate consisting of microorganisms and polysaccharide (glycocalyx) that are produced by microorganisms and adhere to solid surfaces. In the oral cavity, biofilm, called dental plaque, is known as a virulence factor for dental caries. Biofilm is formed and adapts to various environmental factors in the oral cavity. Streptococcus mutans, a cariogenic bacteria, plays an important role in biofilm formation. In this study, we focused on a bacterial two-component system (TCS) as an environmental adaptation factor in S. mutans. We comprehensively evaluated the involvement of TCS in response to various factors associated with the oral cavity using 14 TCS deletion mutants of S. mutans. Furthermore, we evaluated the expression of each TCS in sucrose-dependent biofilm cells of S. mutans. Our findings suggested that multiple TCS play important roles promoting in resistance to environmental stresses and the formation of biofilm.

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Twenty-seven years after the discovery of HIV-1 in 1983, we are still unable to eliminate the virus from infected patients. A highly active antiretroviral therapy (HAART), using combinations of antiretroviral agents, efficiently decreases the HIV-1 load to below the limit of detection, reducing mortality due to HIV-1 infection. Despite the potency of HAART, however, latent HIV-1 infection is established in reservoir of resting CD4⁺ T cells, escaping host immune responses and antiretroviral therapy. HIV-1 latency is thus the main obstacle to eradicating of the virus from infected patients. A causal link between infection by various microbes in HIV-infected individuals and disease progression of AIDS has been documented in the context of the ability of coinfecting microbes and their products to augment HIV-1 replication. Although HIV-related oral lesions are known to be early signs of HIV-1 infection, the causal relationship between periodontal disease and HIV-1 infection has not been elucidated. Recently, we found that the periodontopathic bacterium Porphyromonas gingivalis could induce HIV-1 reactivation via chromatin modification, and that the bacterial metabolites butyric acid is responsible for this effect. Our observations suggest that periodontal diseases could act as a risk factor for HIV-1 reactivation in infected individuals and might contribute to systemic dissemination of the virus. This review attempts to evaluate the current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency, and presents a hypothetic model for the potential role of periodontitis as a risk factor for HIV-1 activation in infected individuals.

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Nitrogen-containing bisphosphonates (NBPs) are widely used as anti-bone resorptive drugs; however, NBPs have inflammatory side effects, including osteomyelitis and osteonecrosis of the jaw. In this paper, we review the effects of alendronate, a typical NBP, on cytokine production by mouse and human cells incubated with Porphyromonas gingivalis or lipid A.
Pretreatment of J774.1 cells, a mouse macrophage-like cell line, with alendronate augments P. gingivalis-induced interleukin (IL)-1β production, but decreases the production of Toll-like receptor (TLR) ligand-induced monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). Furthermore, caspase-1, a promoter of IL-1β production, is activated by treatment with alendronate; however, alendronate directly activates Smad3.
Pretreatment of human peripheral blood mononuclear cells (PBMCs) with alendronate promotes P. gingivalis-induced production of IL-1β and IL-6, but decreases P. gingivalis-induced IL-8 and MCP-1 production. We observed similar results in PBMCs treated with alendronate followed by lipid A. Pretreatment with alendronate did not increase NF-κB activation in PBMCs stimulated with lipid A.
In human gingival fibroblasts, alendronate pretreatment increased lipid A-induced production of IL-6 and IL-8. In addition, pretreatment with alendronate increased NF-κB and Smad3 activation in gingival fibroblasts stimulated with lipid A, and SIS3, a specific inhibitor of Smad3, significantly inhibited alendronate-increased IL-6 and IL-8 production.
These results suggest that alendronate-mediated changes in cytokine production by cells occur via regulation of transcriptional activity, including NF-κB and Smad3, and that this agent may exacerbate periodontitis and jaw osteomyelitis, which are chronic inflammatory diseases caused by high levels of oral bacterial components.

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Adult postnatal stem cells are multipotent and can be experimentally induced to differentiate into various specialized cell lineages. This has generated considerable interest in the arena of stem cell-based therapeutics. The identification of stem cells within the periodontal ligament represents a significant development in this regard. Achieving predictable periodontal regeneration has long been a challenge, and it is known that cells involved in the mechanisms of periodontal wound healing are of mesenchymal stem cell (MSC) type. Thus, periodontal ligament stem cell (PDLSC)-based therapeutics may be a step towards predictable periodontal regeneration. Additionally, PDLSC may have alternative potential applications in hard tissue and tooth engineering. PDLSC may be isolated, grown under tissue culture conditions, expanded, optionally genetically modified and then collected and transplanted. This paper aims to overview the current knowledge, recent developments and methodology regarding PDLSC-based applications.

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We examined the antibacterial effects of cocoa on periodontal pathogenic bacteria, including Porphyromonas gingivalis, Fusobacterium nucleatum and Prevotella intermedia, compared with its effects on indigenous oral streptococci. A colony-forming unit (CFU) assay in the presence and absence of 1.0% and 3.0% (w/v) cocoa revealed that the growth of periodontal pathogenic bacteria was significantly suppressed by cocoa in concentration- and incubation time-dependent manners, although cocoa had no effect on the growth of indigenous streptococci. Methanol- and ethanol-extractable fractions from cocoa were also subjected to the CFU assay to determine and characterize the component (s) responsible for these effects. Fractions containing mainly cocoa polyphenols showed antibacterial effects. After treatment with polyvinylpolypyrrolidone, an absorbent of polyphenols, the methanol-extractable fraction lost its effect. These results suggest that cocoa has significant antibacterial effects against periodontal pathogenic bacteria and that polyphenols are responsible.

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