Journal of Dental Research

We aimed to consolidate all epidemiologic data about untreated caries and subsequently generate internally consistent prevalence and incidence estimates for all countries, 20 age groups, and both sexes for 1990 and 2010. The systematic search of the literature yielded 18,311 unique citations. After screening titles and abstracts, we excluded 10,461 citations as clearly irrelevant to this systematic review, leaving 1,682 for full-text review. Furthermore, 1,373 publications were excluded following the validity assessment. Overall, 192 studies of 1,502,260 children aged 1 to 14 y in 74 countries and 186 studies of 3,265,546 individuals aged 5 y or older in 67 countries were included in separate metaregressions for untreated caries in deciduous and permanent teeth, respectively, using modeling resources from the Global Burden of Disease 2010 study. In 2010, untreated caries in permanent teeth was the most prevalent condition worldwide, affecting 2.4 billion people, and untreated caries in deciduous teeth was the 10th-most prevalent condition, affecting 621 million children worldwide. The global age-standardized prevalence and incidence of untreated caries remained static between 1990 and 2010. There is evidence that the burden of untreated caries is shifting from children to adults, with 3 peaks in prevalence at ages 6, 25, and 70 y. Also, there were considerable variations in prevalence and incidence between regions and countries. Policy makers need to be aware of a predictable increasing burden of untreated caries due to population growth and longevity and a significant decrease in the prevalence of total tooth loss throughout the world from 1990 to 2010.

Bacterial glycosyltransferases play important roles in bacterial fitness and virulence. Oral streptococci have evolved diverse strategies to survive and thrive in the carbohydrate-rich oral cavity. In this review, we discuss 2 important biological processes mediated by 2 distinct groups of glycosyltransferases in oral streptococci that are important for bacterial colonization and virulence. The first process is the glycosylation of highly conserved serine-rich repeat adhesins by a series of glycosyltransferases. Using Streptococcus parasanguinis as a model, we highlight new features of several glycosyltransferases that sequentially modify the serine-rich glycoprotein Fap1. Distinct features of a novel glycosyltransferase fold from a domain of unknown function 1792 are contrasted with common properties of canonical glycosyltransferases. The second biological process we cover is involved in building sticky glucan matrix to establish cariogenic biofilms by an important opportunistic pathogen Streptococcus mutans through the action of a family of 3 glucosyltransferases. We focus on discussing the structural feature of this family as a glycoside hydrolase family of enzymes. While the 2 processes are distinct, they all produce carbohydrate-coated biomolecules, which enable bacteria to stick better in the complex oral microbiome. Understanding the making of the sweet modification presents a unique opportunity to develop novel antiadhesion and antibiofilm strategies to fight infections by oral streptococci and beyond.

Osteoarthritis is a common disease that can cause severe pain and dysfunction in any joint, including the temporomandibular joint (TMJ). TMJ osteoarthritis (TMJOA) is an important subtype in the classification of temporomandibular disorders. TMJOA pathology is characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic inflammation in the synovial tissue. However, the exact pathogenesis and process of TMJOA remain to be understood. An increasing number of studies have recently focused on inflammation and remodeling of subchondral bone during the early stage of TMJOA, which may elucidate the possible mechanism of initiation and progression of TMJOA. The treatment strategy for TMJOA aims at relieving pain, preventing the progression of cartilage and subchondral bone destruction, and restoring joint function. Conservative therapy with nonsteroidal anti-inflammatory drugs, splint, and physical therapy, such as low-energy laser and arthrocentesis, are the most common treatments for TMJOA. These therapies are effective in most cases in relieving the signs and symptoms, but their long-term therapeutic effect on the pathologic articular structure is unsatisfactory. A treatment that can reverse the damage of TMJOA remains unavailable to date. Treatments that prevent the progression of cartilage degradation and subchondral bone damage should be explored, and regeneration for the TMJ may provide the ideal long-term solution. This review summarizes the current understanding of mechanisms underlying the pathogenesis and treatment of TMJOA.

Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro–computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876).

This prospective 3-arm parallel-group randomized clinical trial investigated the effect of supplemental vibrational force on rate of orthodontic tooth alignment with fixed appliances. Eighty-one subjects (40 males, 41 females; mean age, 14.1 y) undergoing first premolar extraction-based fixed appliance treatment were randomly allocated to treatment supplemented with daily use (20 min) of a removable intraoral vibrational device (AcceleDent; OrthoAccel Technologies Inc.; n = 29), an identical nonfunctional (sham) device (n = 25), or fixed appliances only (n = 27). Mandibular study casts were taken at baseline (treatment start: placement of 0.014-in. nickel-titanium arch wire), initial alignment (0.018-in. nickel-titanium arch wire), and final alignment (0.019 x 0.025–in. stainless steel arch wire). Overall mean irregularity index in the mandibular arch at baseline was 8.5 ± 3.8 mm (95% CI, 7.6 to 9.3) with no significant difference between groups (P = 0.73). For the total sample, mean irregularity index at initial alignment was 2.7 ± 2.8 mm (95% CI, 2.2 to 3.4) with no significant difference between groups (P = 0.40). Mean time from baseline to initial alignment was 59 ± 25 d (95% CI, 54.5 to 65.6); from initial to final alignment, 150 ± 62.5 d (95% CI, 136 to 165); and baseline to final alignment, 209 ± 65 d (95% CI, 195 to 224). Kaplan-Meier analysis demonstrated that patterns of alignment were not significantly different among the 3 groups (P = 0.66). Multivariate linear regression for initial and overall alignment rates using initial irregularity index as the covariate showed no significant differences among groups. The most important influence on both initial and overall rates of alignment was initial irregularity (P = 0.1 × 10⁻⁴). This prospective randomized clinical trial found no evidence that supplemental vibrational force can significantly increase the rate of initial tooth movement or reduce the amount of time required to achieve final alignment when used in conjunction with a preadjusted edgewise fixed appliance (ClinicalTrials.gov NCT02314975).

Local anesthesia has made dental treatment more comfortable since 1884, but little is known about associated brain mechanisms. Functional magnetic resonance imaging is a modern neuroimaging tool widely used for investigating human brain activity related to sensory perceptions, including pain. Most brain regions that respond to experimental noxious stimuli have recently been found to react not only to nociception alone, but also to visual, auditory, and other stimuli. Thus, presumed functional attributions have come under scrutiny regarding selective pain processing in the brain. Evidently, innovative approaches are warranted to identify cerebral regions that are nociceptive specific. In this study, we aimed at circumventing known methodological confounders by applying a novel paradigm in 14 volunteers: rather than varying the intensity and thus the salience of painful stimuli, we applied repetitive noxious dental stimuli at constant intensity to the left mandibular canine. During the functional magnetic resonance imaging paradigm, we suppressed the nociceptive barrage by a mental nerve block. Brain activity before and after injection of 4% articaine was compared intraindividually on a group level. Dental pain extinction was observed to correspond to activity reduction in a discrete region of the left posterior insular cortex. These results confirm previous reports demonstrating that direct electrical stimulation of this brain region—but not of others—evokes bodily pain sensations. Hence, our investigation adds further evidence to the notion that the posterior insula plays a unique role in nociceptive processing.

Amelotin (AMTN) is a relatively recently discovered enamel protein that is predominantly expressed by ameloblasts during the maturation stage of amelogenesis and is present at lower levels in the junctional epithelium of erupted teeth. Previous studies have suggested a function of this protein in enamel mineralization and cell attachment. Genetic mouse models have been instrumental in defining the role of many enamel-related proteins, but a genetic mouse model lacking the Amtn gene has not been reported. Here, we describe the generation of amelotin-deficient mice and the analysis of their enamel phenotype in comparison with that of wild-type animals. Ablation of AMTN expression resulted in mechanically inferior enamel of mandibular incisors that showed chipping and fractures at the incisal edge. Enamel mineralization was delayed, resulting in hypomineralized inner enamel and structural defects in the outer enamel. Erupted enamel close to the gingival margin showed increased surface roughness. The expression levels of the enamel matrix proteins AMEL, AMBN, ENAM, and ODAM and the enamel proteases MMP-20 and KLK-4 were not significantly altered, although the expression of KLK-4 was delayed. The morphology of ameloblasts showing prominent Tomes’ processes during the secretory stage was not altered, and there was no indication of disruption of cell structures or activities, but a residual layer, presumably consisting of organic material, remained at the enamel surface close to the gingival margin. The integrity of the dentogingival attachment at the junctional epithelium appeared unaffected by AMTN deficiency. These observations indicate that AMTN plays a subtle yet critical role in enamel biomineralization, particularly during the establishment of the outer and surface enamel layers. This role appears to be largely independent of other enamel proteins.

Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl^-/-) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl^-/- mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl^+/A116T mice to validate this model. Alpl^+/A116T mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl^+/A116T versus wild-type mice. The postcranial skeleton of Alpl^+/A116T mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl^+/A116T mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro–computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl^+/A116T mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies.

In humans, approximately 90% of saliva is secreted by the 3 major salivary glands: the parotid (PG), the submandibular (SMG), and the sublingual glands (SLG). Even though it is known that all 3 major salivary glands secrete saliva by a Cl^--dependent mechanism, salivary secretion rates differ greatly among these glands. The goal of this study was to gain insight into the properties of the ion-transporting pathways in acinar cells that might account for the differences among the major salivary glands. Pilocarpine-induced saliva was simultaneously collected in vivo from the 3 major salivary glands of mice. When normalized by gland weight, the amount of saliva secreted by the PG was more than 2-fold larger than that obtained from the SMG and SLG. At the cellular level, carbachol induced an increase in the intracellular [Ca²⁺] that was more than 2-fold larger in PG and SMG than in SLG acinar cells. Carbachol-stimulated Cl^- efflux and the protein levels of the Ca²⁺-activated Cl^- channel TMEM16A, the major apical Cl^- efflux pathway in salivary acinar cells, were significantly greater in PG compared with SMG and SLG. In addition, we evaluated the transporter activity of the Na⁺-K⁺-2Cl^- cotransporters (NKCC1) and anion exchangers (AE), the 2 primary basolateral Cl^- uptake mechanisms in acinar cells. The SMG NKCC1 activity was about twice that of the PG and more than 12-fold greater than that of the SLG. AE activity was similar in PG and SLG, and both PG and SLG AE activity was about 2-fold larger than that of SMG. In summary, the salivation kinetics of the 3 major glands are distinct, and these differences can be explained by the unique functional properties of each gland related to Cl^- movement, including the transporter activities of the Cl^- uptake and efflux pathways, and intracellular Ca²⁺ mobilization.

The presence of functional autoantibodies against the muscarinic type 3 receptor (M3R) has been reported in primary Sjögren’s syndrome (pSS). However, the pathogenic role of these autoantibodies in pSS development remains to be elucidated. In this experiment, we investigated a pathologic role of pSS autoantibodies (pSS IgG) associated with downregulation of the major histocompatibility complex I (MHC I) molecule with M3R through internalization. Anti-M3R autoantibodies in purified control and pSS IgG were detected using 4 synthesized cyclic M3R peptides by enzyme-linked immunosorbent assay. The binding reactivity of pSS IgG to M3R in situ was analyzed by a dual immunostaining method. Surface expression, interaction, and internalization of M3R with MHC I were analyzed by immunofluorescence confocal microscopy and biochemical assays. Synthetic cyclic peptides M3RP^205-221 and M3RP^520-527 showed significantly high reactivity with pSS IgG compared to the control IgG or the other 3 peptides (P < 0.05). Significantly high reactivity of pSS IgG to M3R in situ was observed. PSS IgG increased the interaction of membrane M3R with MHC I and induced their internalization in primary human submandibular gland cells. The pSS IgG-induced internalization of M3R with MHC I was significantly inhibited by the cholesterol-sequestering drug filipin. Our novel finding—namely, strong downregulation of the membrane MHC I with M3R through internalization of the cholesterol-rich microdomain associating with anti-M3R autoantibodies—could be an important mechanism contributing to the impaired salivation seen in pSS and linking secretory hypofunction to autoimmune pathogenesis.

This study investigated the relevance between pulp vitality and autophagy in aged human dental pulp cells (HDPCs) and whether peroxisome proliferator-activated receptor gamma (PPARγ) affects autophagy regulation for homeostasis in the aging progress. In vivo experiments were used in human and Sprague-Dawley rat teeth obtained from young and adult individuals. Aging- and autophagy-related molecules were determined by immunohistochemistry and hematoxylin and eosin staining. HDPCs were serially subcultured until spontaneously arrested for in vitro aging, and the replication deficiency adenovirus was introduced for PPARγ overexpression. Subsequently, the effect of PPARγ on regulation of autophagy molecules, mitochondria activity, and cell viability was assessed using Western blotting, confocal microscopy, and the MTT assay, respectively. In adult pulp tissue, autophagy molecules (autophagy protein 5, microtubule-associated protein 1A/1B light chain, and Beclin-1) were increased, but aging-related (PPARγ and heme oxygenase 1 [HO-1]) and dentinogenesis (dentin sialophosphoprotein and dentin matrix acidic phosphoprotein) molecules were decreased. In aged HDPCs, autophagy and intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were increased, while PPARγ and HO-1 were decreased. Under stimulation with lipopolysaccharide, autophagy- and aging-related molecules were differentially expressed between young and aged cells. PPARγ induced HO-1 and autophagy molecules but reduced inflammatory molecules in aged cells. In addition, PPARγ activated strong mitochondrial activity and cell viability in aging cells. Inhibition of HO-1 by tin protoporphyrin IX exacerbated autophagy and mitochondrial activity as well as cell viability in young cells. This study indicates that PPARγ maintains pulp homeostasis through the regulation of autophagy molecules during the life span of HDPCs.

While nuclear medicine has been proven clinically effective for examination of the change in bone turnover as a result of stress injury, quantitative correlation between tracer uptake and mechanical stimulation in the human jawbone remains unclear. This study aimed to investigate the relationship between bone metabolism observed by 18F-fluoride positron emission tomography (PET) images and mechanical stimuli obtained by finite element analysis (FEA) in the residual ridge induced by the insertion of a removable partial denture (RPD). An 18F-fluoride PET/CT (computerized tomography) scan was performed to assess the change of bone metabolism in the residual ridge under the denture before and after RPD treatment. Corresponding patient-specific 3D finite element (FE) models were created from CT images. Boundary conditions were prescribed by the modeling of condylar contacts, and muscular forces were derived from the occlusal forces measured in vivo to generate mechanobiological reactions. Different mechanobiological stimuli, e.g., equivalent von Mises stress (VMS), equivalent strain (EQV), and strain energy density (SED), determined from nonlinear FEA, were quantified and compared with the standardized uptake values (SUVs) of PET. Application of increased occlusal force after RPD insertion induced higher mechanical stimuli in the residual bone. Accordingly, SUV increased in the region of residual ridge with higher mechanical stimuli. Thus, with SUV, a clear correlation was observed with VMS and SED in the cancellous bone, especially after RPD insertion (R² > 0.8, P < 0.001). This study revealed a good correlation between bone metabolism and mechanical stimuli induced by RPD insertion. From this patient-specific study, it was shown that metabolic change detected by PET in the loaded bone, in a much shorter duration than conventional x-ray assessment, is associated with mechanical stimuli. The nondestructive nature of PET/CT scans and FEA could potentially provide a new method for clinical examination and monitoring of prosthetically driven bone remodeling.