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1.  The Circadian Clock in Oral Health and Diseases 
Journal of Dental Research  2014;93(1):27-35.
Most physiological processes in mammals display circadian rhythms that are driven by the endogenous circadian clock. This clock is comprised of a central component located in the hypothalamic suprachiasmatic nucleus and subordinate clocks in peripheral tissues. Circadian rhythms sustain 24-hour oscillations of a large number of master genes controlling the correct timing and synchronization of diverse physiological and metabolic processes within our bodies. This complex regulatory network provides an important communication link between our brain and several peripheral organs and tissues. At the molecular level, circadian oscillations of gene expression are regulated by a family of transcription factors called “clock genes”. Dysregulation of clock gene expression results in diverse human pathological conditions, including autoimmune diseases and cancer. There is increasing evidence that the circadian clock affects tooth development, salivary gland and oral epithelium homeostasis, and saliva production. This review summarizes current knowledge of the roles of clock genes in the formation and maintenance of oral tissues, and discusses potential links between “oral clocks” and diseases such as head and neck cancer and Sjögren’s syndrome.
doi:10.1177/0022034513505768
PMCID: PMC3865791  PMID: 24065634
autoimmune diseases; salivary glands; clock genes; tooth; oral cancer; Sjögren’s syndrome
2.  Standardization and Safety of Alveolar Bone–derived Stem Cell Isolation 
Journal of Dental Research  2014;93(1):55-61.
Cell therapies utilizing mesenchymal stem cells (MSCs) could overcome limitations of traditional treatments for reconstructing craniofacial tissues. This large-scale study explored a standardized methodology for the isolation and clinical-scale expansion of alveolar bone marrow–derived MSCs (aBMSCs). We harvested 103 alveolar bone marrow samples from 45 patients using 1 of 3 standardized methodologies. Following aBMSC isolation, cells were characterized through cell-surface marker expression and lineage-specific differentiation. Long-term cultures (> 50 population doublings [PDs]) were evaluated for transformational changes through senescence, gene expression, and karyotyping. Finally, aBMSC bone-forming potential was determined in vivo. More than 0.5 cc of bone marrow was needed to predictably isolate aBMSCs, and, regardless of methodology for harvest, cell-surface marker expression of CD73, CD90, CD105, and Stro-1 was similar for aBMSCs, being 89.8%, 98.8%, 93.8%, and 3.2%, respectively; all cells were negative for CD11b, CD19, and CD45. aBMSCs exhibited multipotency, and karyotypes were normal up to 30 PDs, with significant cell senescence beginning following 35 PDs. Additionally, aBMSCs induced ectopic bone formation following subcutaneous transplantation into mice. These findings demonstrate a predictable approach for the isolation and safe clinical-scale expansion of aBMSCs, and thus, their clinical use could be considered for craniofacial regenerative therapies.
doi:10.1177/0022034513510530
PMCID: PMC3865792  PMID: 24170370
mesenchymal stem cells; bone marrow; cell therapy; craniofacial tissue engineering; cultured cell; bone marrow cells
3.  Barrier Formation 
Journal of Dental Research  2014;93(1):96-102.
Enamel fluorosis is an irreversible structural enamel defect following exposure to supraoptimal levels of fluoride during amelogenesis. We hypothesized that fluorosis is associated with excess release of protons during formation of hypermineralized lines in the mineralizing enamel matrix. We tested this concept by analyzing fluorotic enamel defects in wild-type mice and mice deficient in anion exchanger-2a,b (Ae2a,b), a transmembrane protein in maturation ameloblasts that exchanges extracellular Cl− for bicarbonate. Defects were more pronounced in fluorotic Ae2a,b −/− mice than in fluorotic heterozygous or wild-type mice. Phenotypes included a hypermineralized surface, extensive subsurface hypomineralization, and multiple hypermineralized lines in deeper enamel. Mineral content decreased in all fluoride-exposed and Ae2a,b−/− mice and was strongly correlated with Cl−. Exposure of enamel surfaces underlying maturation-stage ameloblasts to pH indicator dyes suggested the presence of diffusion barriers in fluorotic enamel. These results support the concept that fluoride stimulates hypermineralization at the mineralization front. This causes increased release of protons, which ameloblasts respond to by secreting more bicarbonates at the expense of Cl− levels in enamel. The fluoride-induced hypermineralized lines may form barriers that impede diffusion of proteins and mineral ions into the subsurface layers, thereby delaying biomineralization and causing retention of enamel matrix proteins.
doi:10.1177/0022034513510944
PMCID: PMC3865793  PMID: 24170372
pH regulation; Slc4a2; chloride; quantitative X-ray microanalysis; hypermineralization; hypomineralization
4.  FAM20A Mutations Associated with Enamel Renal Syndrome 
Journal of Dental Research  2014;93(1):42-48.
We identified two families with an autosomal-recessive disorder manifested by severe enamel hypoplasia, delayed and failed tooth eruption, misshapen teeth, intrapulpal calcifications, and localized gingival hyperplasia. Genetic analyses identified novel FAM20A mutations associated with the disease phenotype in both families. The proband of Family 1 had an altered splice junction in Intron 1 (g.502011G>C; c.405-1G>C) and a missense mutation in Exon 8 (g.65094G>A; c.1207G>A; p.D403N). The missense mutation is notable because D403 is strictly conserved among FAM20A homologues, and the corresponding defect in FAM20C caused osteosclerotic bone dysplasia and a loss of kinase activity. The proband at age 12 yrs tested negative for nephrocalcinosis. The proband and her affected father in Family 2 were homozygous for a single nucleotide deletion that altered a splice junction in Intron 10 (g.66622del; c.1361+4del). Minigene analyses demonstrated that this alteration precluded normal splicing. Immunohistochemistry (IHC) of mouse maxillary first molars localized FAM20A in secretory-stage ameloblasts, in odontoblasts, and in the eruption pathway. IHC of kidneys localized FAM20A in the renal tubules. We conclude that FAM20A is likely a secretory pathway kinase and that loss-of-function mutations cause pathology where its phosphorylations are necessary for normal development or homeostasis.
doi:10.1177/0022034513512653
PMCID: PMC3865794  PMID: 24196488
amelogenesis imperfecta; gingival hyperplasia; enamel; tooth; delayed eruption; nephrocalcinosis
5.  Contribution of Mesenchymal Proliferation in Tooth Root Morphogenesis 
Journal of Dental Research  2014;93(1):78-83.
In mouse tooth development, the roots of the first lower molar develop after crown formation to form 2 cylindrical roots by post-natal day 5. This study compared the morphogenesis and cellular events of the mesial-root-forming (MRF) and bifurcation-forming (BF) regions, located in the mesial and center of the first lower molar, to better define the developmental mechanisms involved in multi-rooted tooth formation. We found that the mesenchyme in the MRF showed relatively higher proliferation than the bifurcation region. This suggested that spatially regulated mesenchymal proliferation is required for creating cylindrical root structure. The mechanism may involve the mesenchyme forming a physical barrier to epithelial invagination of Hertwig’s epithelial root sheath. To test these ideas, we cultured roots in the presence of pharmacological inhibitors of microtubule and actin polymerization, nocodazole and cytochalasin-D. Cytochalasin D also inhibits proliferation in epithelium and mesenchyme. Both drugs resulted in altered morphological changes in the tooth root structures. In particular, the nocodazole- and cytochalasin-D-treated specimens showed a loss of root diameter and formation of a single-root, respectively. Immunolocalization and three-dimensional reconstruction results confirmed these mesenchymal cellular events, with higher proliferation in MRF in multi-rooted tooth formation.
doi:10.1177/0022034513511247
PMCID: PMC3872847  PMID: 24155265
tooth development; molar; tooth root; odontogenesis; cell proliferation; histochemistry
6.  Effect on Caries of Restricting Sugars Intake 
Journal of Dental Research  2014;93(1):8-18.
A systematic review of studies in humans was conducted to update evidence on the association between the amount of sugars intake and dental caries and on the effect of restricting sugars intake to < 10% and < 5% energy (E) on caries to inform the updating of World Health Organization guidelines on sugars consumption. Data sources included MEDLINE, EMBASE, Cochrane Database, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences, China National Knowledge Infrastructure, Wanfang, and South African Department of Health. Eligible studies reported the absolute amount of sugars and dental caries, measured as prevalence, incidence, or severity. The review was conducted and reported in accordance with the PRISMA statement, and the evidence was assessed according to GRADE Working Group guidelines. From 5,990 papers identified, 55 studies were eligible – 3 intervention, 8 cohort, 20 population, and 24 cross-sectional. Data variability limited meta-analysis. Of the studies, 42 out of 50 of those in children and 5 out of 5 in adults reported at least one positive association between sugars and caries. There is evidence of moderate quality showing that caries is lower when free-sugars intake is < 10% E. With the < 5% E cut-off, a significant relationship was observed, but the evidence was judged to be of very low quality. The findings are relevant to minimizing caries risk throughout the life course.
doi:10.1177/0022034513508954
PMCID: PMC3872848  PMID: 24323509
nutrition policy; oral health; sucrose; carbohydrates; adult; child
7.  High-temperature-pressure Polymerized Resin-infiltrated Ceramic Networks 
Journal of Dental Research  2014;93(1):62-67.
The aim of this study was to produce composite blocks (CB) for CAD/CAM applications by high-temperature-pressure (HT/HP) polymerization of resin-infiltrated glass-ceramic networks. The effect of network sintering and the absence/presence of initiator was investigated. Mechanical properties were determined and compared with those of Paradigm MZ100 (3M ESPE) blocks and HT/HP polymerized experimental “classic” CB, in which the filler had been incorporated by conventional mixing. The networks were made   from glass-ceramic powder (VITA Zahnfabrik) formed by slip casting and were either sintered or not. They were silanized, infiltrated by urethane dimethacrylate, with or without initiator, and polymerized under HT/HP (300 MPa, 180°C) to obtain resin-infiltrated glass-ceramic network (RIGCN) CB. HT/HP polymerized CB were also made from an experimental “classic” composite. Flexural strength (σf), fracture toughness (KIC), and Vickers hardness were determined and analyzed by one- or two-way analysis of variance (ANOVA), Scheffé multiple-means comparisons (α = 0.05), and Weibull statistics (for σf). Fractured surfaces were characterized with scanning electron microscopy. The mechanical properties of RIGCN CB were significantly higher. Sintering induced significant increases in σf and hardness, while the initiator significantly decreased hardness. The results suggested that RIGCN and HT/HP polymerization could be used to obtain CB with superior mechanical properties, suitable for CAD/CAM applications.
doi:10.1177/0022034513511972
PMCID: PMC3872849  PMID: 24186559
composite materials; CAD; glass-ceramics; polymers; materials science; prosthodontics
8.  Cooperative Effects of FGF-2 and VEGF-A in Periodontal Ligament Cells 
Journal of Dental Research  2014;93(1):89-95.
We previously demonstrated that topical application of fibroblast growth factor (FGF)-2 enhanced periodontal tissue regeneration. Although angiogenesis is a crucial event for tissue regeneration, the mechanism(s) by which topically applied FGF-2 induces angiogenesis in periodontal tissues has not been fully clarified. In this study, we investigated whether FGF-2 could induce vascular endothelial growth factor (VEGF)-A expression in periodontal ligament (PDL) cells and whether cell-to-cell interactions between PDL cells and endothelial cells could stimulate angiogenesis. FGF-2 induced VEGF-A secretion from MPDL22 cells (mouse periodontal ligament cell line) in a dose-dependent manner. Transwell and wound-healing assays revealed that co-stimulation with FGF-2 plus VEGF-A synergistically stimulated the migration of MPDL22 cells. Interestingly, co-culture of MPDL22 cells with bEnd5 cells (mouse endothelial cell line) also stimulated VEGF-A production from MPDL22 cells and tube formation by bEnd5 cells. Furthermore, time-lapse analysis revealed that MPDL22 cells migrated close to the tube-forming bEnd5 cells, mimicking pericytes. Thus, FGF-2 induces VEGF-A expression in PDL cells and induces angiogenesis in combination with VEGF-A. Cell-to-cell interactions with PDL cells also facilitate angiogenesis.
doi:10.1177/0022034513511640
PMCID: PMC3872850  PMID: 24186558
growth factors; cell communication; endothelial cells; tissue regeneration; cell migration; pericytes
9.  Comparison of Long-term Survival of Implants and Endodontically Treated Teeth 
Journal of Dental Research  2014;93(1):19-26.
The outcomes of both dental implants and endodontically treated teeth have been extensively studied. However, there is still a great controversy over when to keep a natural tooth and when to extract it for a dental implant. This article reviews the benefits and disadvantages of both treatment options and discusses success vs. survival outcomes, as well as the impact of technical advances for modern endodontics and endodontic microsurgery on the long-term prognosis of tooth retention.
doi:10.1177/0022034513504782
PMCID: PMC3872851  PMID: 24065635
dental implants; endodontic therapy; oral health; outcome; systematic review; treatment planning
10.  Sodium Fluoride Inhibits MMP-2 and MMP-9 
Journal of Dental Research  2014;93(1):74-77.
The importance of fluoride (F) in preventing dental caries by favorably interfering in the demineralization-remineralization processes is well-established, but its ability to inhibit matrix metalloproteinases (MMPs), which could also help to prevent dentin caries, has not been investigated. This study assessed the ability of F to inhibit salivary and purified human gelatinases MMPs-2 and -9. Saliva was collected from 10 healthy individuals. Pooled saliva was centrifuged, and supernatants were incubated for 1 hr at 37°C and subjected to zymography. Sodium fluoride (50-275 ppm F) was added to the incubation buffer. The reversibility of the inhibition of MMPs-2 and -9 by NaF was tested by the addition of NaF (250-5,000 ppm F) to the incubation buffer, after which an additional incubation was performed in the absence of F. F decreased the activities of pro- and active forms of salivary and purified human MMPs in a dose-response manner. Purified gelatinases were completely inhibited by 200 ppm F (IC50 = 100 and 75 ppm F for MMPs-2 and -9, respectively), and salivary MMP-9 by 275 ppm F (IC50 = 200 ppm F). Inhibition was partially reversible at 250-1,500 ppm F, but was irreversible at 5,000 ppm F. This is the first study to describe the ability of NaF to inhibit MMPs completely.
doi:10.1177/0022034513511820
PMCID: PMC3872852  PMID: 24196489
fluorides; matrix metalloproteinase-2; matrix matalloproteinase-9; dentin; inhibition; extracellular matrix
11.  Adhesion Forces and Composition of Planktonic and Adhering Oral Microbiomes 
Journal of Dental Research  2014;93(1):84-88.
The oral microbiome consists of a planktonic microbiome residing in saliva and an adhering microbiome (the biofilm adhering to oral hard and soft tissues). Here we hypothesized that possible differences in microbial composition of the planktonic and adhering oral microbiome on teeth can be related to the forces by which different bacterial species are attracted to the tooth surface. The relative presence of 7 oral bacterial species in saliva and biofilm collected from 10 healthy human volunteers was determined twice in each volunteer by denaturing-gradient-gel electrophoresis. Analysis of both microbiomes showed complete separation of the planktonic from the adhering oral microbiome. Next, adhesion forces of corresponding bacterial strains with saliva-coated enamel surfaces were measured by atomic force microscopy. Species that were found predominantly in the adhering microbiome had significantly higher adhesion forces to saliva-coated enamel (-0.60 to -1.05 nN) than did species mostly present in the planktonic microbiome (-0.40 to -0.55 nN). It is concluded that differences in composition of the planktonic and the adhering oral microbiome are due to small differences in the forces by which strains adhere to saliva-coated enamel, providing an important step in understanding site- and material-specific differences in the composition of biofilms in the oral cavity.
doi:10.1177/0022034513511822
PMCID: PMC3872853  PMID: 24186560
atomic force microscopy; denaturing gradient gel electrophoresis; biofilm; dental plaque; saliva; bacterial adhesion
12.  Body Mass Index as a Predictive Factor of Periodontal Therapy Outcomes 
Journal of Dental Research  2014;93(1):49-54.
Body mass index (BMI) and obesity are associated with the prevalence, extent, and severity of periodontitis. This study investigated the predictive role of overweight/obesity on clinical response following non-surgical periodontal therapy in patients with severe periodontitis. Two hundred sixty adults received an intensive course of non-surgical periodontal therapy. Periodontal status at baseline and 2 months was based upon probing pocket depths (PPD), clinical attachment levels (CAL), and whole-mouth gingival bleeding (FMBS) as assessed by two calibrated examiners. Generalized estimating equations (GEE) were used to estimate the impact of BMI and overweight/obesity on periodontal treatment response while controlling for baseline status, age, smoking status (smoker or non-smoker), and full-mouth dental plaque score. BMI (continuous variable) and obesity (vs. normal weight) were associated with worse mean PPD (p < .005), percentage of PPD > 4 mm (p = .01), but not with FMBS (p > .05) or CAL (p > .05) at 2 months, independent of age, smoking status, or dental plaque levels. The magnitude of this association was similar to that of smoking, which was also linked to a worse clinical periodontal outcome (p < .01). BMI and obesity appear to be independent predictors of poor response following non-surgical periodontal therapy.
doi:10.1177/0022034513511084
PMCID: PMC3872854  PMID: 24165943
obesity; overweight; periodontitis; wound healing; chronic disease; prognosis
13.  Gender Equity in Dental Academics 
Journal of Dental Research  2014;93(1):5-7.
doi:10.1177/0022034513510178
PMCID: PMC3872855  PMID: 24144534
gender gap; dental academia; faculty retention; academic leadership; salary inequality; tenure policy
14.  Removal of Interproximal Dental Biofilms by High-velocity Water Microdrops 
Journal of Dental Research  2014;93(1):68-73.
The influence of the impact of a high-velocity water microdrop on the detachment of Streptococcus mutans UA159 biofilms from the interproximal (IP) space of teeth in a training typodont was studied experimentally and computationally. Twelve-day-old S. mutans biofilms in the IP space were exposed to a prototype AirFloss delivering 115 µL water at a maximum exit velocity of 60 m/sec in a 30-msec burst. Using confocal microscopy and image analysis, we obtained quantitative measurements of the percentage removal of biofilms from different locations in the IP space. The 3D geometry of the typodont and the IP spaces was obtained by micro-computed tomography (µ-CT) imaging. We performed computational fluid dynamics (CFD) simulations to calculate the wall shear stress (τw) distribution caused by the drops on the tooth surface. A qualitative agreement and a quantitative relationship between experiments and simulations were achieved. The wall shear stress (τw) generated by the prototype AirFloss and its spatial distribution on the teeth surface played a key role in dictating the efficacy of biofilm removal in the IP space.
doi:10.1177/0022034513510945
PMCID: PMC3872856  PMID: 24170371
oral hygiene; Streptococcus mutans; micro-computed tomography; microscopy; interproximal cleaning; dental plaque
15.  Randomized Control Trial of Composite Cuspal Restorations 
Journal of Dental Research  2014;93(1):36-41.
The objective of this randomized control trial was to compare the five-year clinical performance of direct and indirect resin composite restorations replacing cusps. In 157 patients, 176 restorations were made to restore maxillary premolars with Class II cavities and one missing cusp. Ninety-two direct and 84 indirect resin composite restorations were placed by two operators, following a strict protocol. Treatment technique and operator were assigned randomly. Follow-up period was at least 4.5 yrs. Survival rates were determined with time to reparable failure and complete failure as endpoints. Kaplan-Meier five-year survival rates were 86.6% (SE 0.27%) for reparable failure and 87.2% (SE 0.27%) for complete failure. Differences between survival rates of direct and indirect restorations [89.9% (SE 0.34%) vs. 83.2% (SE 0.42%) for reparable failure and 91.2% (SE 0.32%) vs. 83.2% (SE 0.42%) for complete failure] were not statistically significant (p = .23 for reparable failure; p = .15 for complete failure). Mode of failure was predominantly adhesive. The results suggest that direct and indirect techniques provide comparable results over the long term (trial registration number: ISRCTN29200848).
doi:10.1177/0022034513510946
PMCID: PMC3872857  PMID: 24155264
clinical studies/trials; composite materials; prosthetic dentistry/prosthodontics; restorative dentistry; restorative materials; operative dentistry
16.  Patient-specific Analysis of Periodontal and Peri-implant Microbiomes 
Journal of Dental Research  2013;92(12 Suppl):168S-175S.
Periodontally involved teeth have been implicated as ‘microbial reservoirs’ in the etiology of peri-implant diseases. Therefore, the purpose of this investigation was to use a deep-sequencing approach to identify the degree of congruence between adjacent peri-implant and periodontal microbiomes in states of health and disease. Subgingival and peri-implant biofilm samples were collected from 81 partially edentulous individuals with periodontal and peri-implant health and disease. Bacterial DNA was isolated, and the 16S rRNA gene was amplified and sequenced by pyrotag sequencing. Chimera-depleted sequences were compared against a locally hosted curated database for bacterial identification. Statistical significance was determined by paired Student’s t tests between tooth-implant pairs. The 1.9 million sequences identified represented 523 species. Sixty percent of individuals shared less than 50% of all species between their periodontal and peri-implant biofilms, and 85% of individuals shared less than 8% of abundant species between tooth and implant. Additionally, the periodontal microbiome demonstrated significantly higher diversity than the implant, and distinct bacterial lineages were associated with health and disease in each ecosystem. Analysis of our data suggests that simple geographic proximity is not a sufficient determinant of colonization of topographically distinct niches, and that the peri-implant and periodontal microbiomes represent microbiologically distinct ecosystems.
doi:10.1177/0022034513504950
PMCID: PMC3827621  PMID: 24158341
dental implants; phylogenetic biogeography; peri-implantitis; periodontitis; computational biology; biofilms
17.  Genetic Networks in Osseointegration 
Journal of Dental Research  2013;92(12 Suppl):109S-118S.
Osseointegration-based dental implants have become a well-accepted treatment modality for complete and partial edentulism. The success of this treatment largely depends on the stable integration and maintenance of implant fixtures in alveolar bone; however, the molecular and cellular mechanisms regulating this unique tissue reaction have not yet been fully uncovered. Radiographic and histologic observations suggest the sustained retention of peri-implant bone without an apparent susceptibility to catabolic bone remodeling; therefore, implant-induced bone formation continues to be intensively investigated. Increasing numbers of whole-genome transcriptome studies suggest complex molecular pathways that may play putative roles in osseointegration. This review highlights genetic networks related to bone quality, the transient chondrogenic phase, the vitamin D axis, and the peripheral circadian rhythm to elute the regulatory mechanisms underlying the establishment and maintenance of osseointegration.
doi:10.1177/0022034513504928
PMCID: PMC3827622  PMID: 24158334
dental implants; bone remodeling; gene expression; microarray analysis; cartilage matrix protein; circadian rhythm
18.  The Exopolysaccharide Matrix 
Journal of Dental Research  2013;92(12):1065-1073.
Many infectious diseases in humans are caused or exacerbated by biofilms. Dental caries is a prime example of a biofilm-dependent disease, resulting from interactions of microorganisms, host factors, and diet (sugars), which modulate the dynamic formation of biofilms on tooth surfaces. All biofilms have a microbial-derived extracellular matrix as an essential constituent. The exopolysaccharides formed through interactions between sucrose- (and starch-) and Streptococcus mutans-derived exoenzymes present in the pellicle and on microbial surfaces (including non-mutans) provide binding sites for cariogenic and other organisms. The polymers formed in situ enmesh the microorganisms while forming a matrix facilitating the assembly of three-dimensional (3D) multicellular structures that encompass a series of microenvironments and are firmly attached to teeth. The metabolic activity of microbes embedded in this exopolysaccharide-rich and diffusion-limiting matrix leads to acidification of the milieu and, eventually, acid-dissolution of enamel. Here, we discuss recent advances concerning spatio-temporal development of the exopolysaccharide matrix and its essential role in the pathogenesis of dental caries. We focus on how the matrix serves as a 3D scaffold for biofilm assembly while creating spatial heterogeneities and low-pH microenvironments/niches. Further understanding on how the matrix modulates microbial activity and virulence expression could lead to new approaches to control cariogenic biofilms.
doi:10.1177/0022034513504218
PMCID: PMC3834652  PMID: 24045647
dental caries; Streptococcus mutans; glucosyltransferases; extracellular matrix; pH microenvironment; heterogeneity
19.  Molecular Differences between Chronic and Aggressive Periodontitis 
Journal of Dental Research  2013;92(12):1081-1088.
The 2 major forms of periodontitis, chronic (CP) and aggressive (AgP), do not display sufficiently distinct histopathological characteristics or microbiological/immunological features. We used molecular profiling to explore biological differences between CP and AgP and subsequently carried out supervised classification using machine-learning algorithms including an internal validation. We used whole-genome gene expression profiles from 310 ‘healthy’ or ‘diseased’ gingival tissue biopsies from 120 systemically healthy non-smokers, 65 with CP and 55 with AgP, each contributing with ≥ 2 ‘diseased’ gingival papillae (n = 241; with bleeding-on-probing, probing depth ≥ 4 mm, and clinical attachment loss ≥ 3 mm), and, when available, a ‘healthy’ papilla (n = 69; no bleeding-on-probing, probing depth ≤ 4 mm, and clinical attachment loss ≤ 4 mm). Our analyses revealed limited differences between the gingival tissue transcriptional profiles of AgP and CP, with genes related to immune responses, apoptosis, and signal transduction overexpressed in AgP, and genes related to epithelial integrity and metabolism overexpressed in CP. Different classifying algorithms discriminated CP from AgP with an area under the curve ranging from 0.63 to 0.99. The small differences in gene expression and the highly variable classifier performance suggest limited dissimilarities between established AgP and CP lesions. Future analyses may facilitate the development of a novel, ‘intrinsic’ classification of periodontitis based on molecular profiling.
doi:10.1177/0022034513506011
PMCID: PMC3834653  PMID: 24122488
pathogenesis; gene expression; transcriptome; microarray analysis; classification; machine learning
20.  M180 Amelogenin Processed by MMP20 is Sufficient for Decussating Murine Enamel 
Journal of Dental Research  2013;92(12):1118-1122.
Amelogenin (AMELX) and matrix metalloproteinase-20 (MMP20) are essential for proper enamel development. Amelx and Mmp20 mutations cause amelogenesis imperfecta. MMP20, a protease secreted by ameloblasts, is responsible for processing enamel proteins, including AMELX, during the secretory stage of enamel formation. Of at least 16 different amelogenin splice products, the most abundant isoform found in murine ameloblasts and developing enamel is the M180 protein. To understand the role of MMP20 processing of M180 AMELX, we generated AmelxKO/Mmp20KO (DKO) mice with an amelogenin (M180Tg) transgene. We analyzed the enamel phenotype by SEM to determine enamel structure and thickness, µCT, and by nanoindentation to quantify enamel mechanical properties. M180Tg/DKO mouse enamel had 37% of the hardness of M180Tg/AmelxKO teeth and demonstrated a complete lack of normal prismatic architecture. Although molar enamel of M180Tg/AmelxKO mice was thinner than WT, it had similar mechanical properties and decussating enamel prisms, which were abolished by the loss of MMP20 in the M180Tg/DKO mice. Retention of the C-terminus or complete lack of this domain is unable to rescue amelogenin null enamel. We conclude that among amelogenins, M180 alone is sufficient for normal enamel mechanical properties and prism patterns, but that additional amelogenin splice products are required to restore enamel thickness.
doi:10.1177/0022034513506444
PMCID: PMC3834654  PMID: 24072097
matrix metalloproteinase-20; knockout mouse; transgenic mouse; amelogenesis; imperfecta; ameloblasts; tooth calcification
21.  MMP20 Modulates Cadherin Expression in Ameloblasts as Enamel Develops 
Journal of Dental Research  2013;92(12):1123-1128.
Matrix metalloproteinase-20 (enamelysin, MMP20) is essential for dental enamel development. Seven different MMP20 mutations in humans cause non-syndromic enamel malformations, termed amelogenesis imperfecta, and ablation of Mmp20 in mice results in thin brittle enamel with a dysplastic rod pattern. Healthy enamel formation requires the sliding movement of ameloblasts in rows during the secretory stage of development. This is essential for formation of the characteristic decussating enamel rod pattern observed in rodents, and this is also when MMP20 is secreted into the enamel matrix. Therefore, we propose that MMP20 facilitates ameloblast movement by cleaving ameloblast cell-cell contacts. Here we show that MMP20 cleaves the extracellular domains of the E- and N-cadherin adherens junction proteins, that both E- and N-cadherin transcripts are expressed at significantly higher levels in Mmp20 null vs. wild-type (WT) mice, and that in Mmp20 ablated mice, high-level ameloblast N-cadherin expression persists during the maturation stage of development. Furthermore, we show that E-cadherin gene expression is down-regulated from the pre-secretory to the secretory stage, while N-cadherin levels are up-regulated. This E- to N-cadherin switch supports epithelial migration in other tissues and may be an important event necessary for the ameloblasts to start moving in rows that slide by one another.
doi:10.1177/0022034513506581
PMCID: PMC3834655  PMID: 24067343
enamel biomineralization/formation; matrix metalloproteinases (MMPs); gene expression; cadherins; ameloblast; junctional complexes
22.  Micronutrients and Oral Clefts 
Journal of Dental Research  2013;92(12):1089-1094.
Little is known about oral clefts in developing countries. We aimed to identify micronutrient-related and environmental risk factors for oral clefts in Thailand. We tested hypotheses that maternal exposure during the periconceptional period to multivitamins or liver consumption would decrease cleft lip with or without cleft palate (CL ± P) risk and that menstrual regulation supplements would increase CL ± P risk. We conducted a multisite hospital-based case-control study in Thailand. We enrolled cases with CL ± P and 2 live births as controls at birth from the same hospital. Mothers completed a questionnaire. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Eighty-six cases and 172 controls were enrolled. Mothers who took a vitamin (adjusted OR, 0.39; 95% CI: 0.16, 0.94) or ate liver (adjusted OR, 0.26; 95% CI: 0.12, 0.57) were less likely than those who did not to have an affected child. Mothers who took a menstrual regulation supplement were more likely than mothers who did not to have an affected child. Findings did not differ for infants with a family history of other anomalies or with isolated CL ± P. If replicated, our finding that liver decreases CL ± P risk could offer a low-cost primary prevention strategy.
doi:10.1177/0022034513507452
PMCID: PMC3834656  PMID: 24097855
cleft lip; cleft palate; multivitamin; supplements; vitamins; epidemiology
23.  Integrating Research into Dental Student Training 
Journal of Dental Research  2013;92(12):1053-1055.
The integration of research into dental education is necessary to ensure that evidence-based practice reaches the clinical setting and that dentistry remains a scientifically driven health profession. Consequently, dental accreditation standards in the United States and Canada require dental schools to integrate research components into curricula. Organizations (e.g., NIDCR, ADEA, AADR, IADR, and NSRG) provide some opportunities for dental students to experience research. Assessment of the integration of research into dental curricula suggests that US students are interested in learning and utilizing evidence-based practice, but lack adequate time for research participation. Records show limited student involvement in research organizations internationally (i.e., AADR and IADR). Vague accreditation standards and limited research opportunities outside of dental schools may be barriers. We lack an understanding of the status of integration of research into dental curricula internationally, but predict that similar issues exist. We propose that dental institutions consider implementing the following: (1) curriculum components to assess the use of evidence-based practice, (2) faculty and student seminars for discussing evidence-based practice, (3) subsidization of student membership in dental research organizations (e.g., AADR and IADR), and (4) sponsorship of students as institutional representatives at annual research meetings (e.g., IADR, AADR, ADA, and ADEA meetings), with subsequent school-wide dissemination of knowledge attained from attendance.
doi:10.1177/0022034513508557
PMCID: PMC3834657  PMID: 24114666
dental education; evidence-based dentistry; dental research; professional education; curriculum; society
24.  Retained Asymptomatic Third Molars and Risk for Second Molar Pathology 
Journal of Dental Research  2013;92(12):1095-1099.
Prophylactic extraction of unerupted asymptomatic third molars is the most common oral surgery procedure in the United States. However, limited evidence exists to justify its costs and associated morbidity. We analyzed data collected over 25 years from 416 adult men enrolled in the Veterans Affairs Dental Longitudinal Study to evaluate the association of retained asymptomatic third molars with risk of adjacent second molar pathology (caries and/or periodontitis), based on third molar status (i.e., absent, erupted, or unerupted). Unerupted molars were further categorized as either “soft tissue” or “bony” impacted. We found that the lowest prevalence and incidence of second molar pathology occurred when the adjacent third molar was absent. The presence of a third molar that was soft tissue impacted increased the risk of incident second molar pathology 4.88-fold (95% confidence interval: 2.62, 9.08). Having an erupted or “bony” impacted third molar increased the risk of incident second molar pathology by 1.74 (95% confidence interval: 1.34, 2.25) and 2.16 (95% confidence interval: 1.56, 2.99), respectively. The retention of third molars is associated with increased risk of second molar pathology in middle-aged and older adult men.
doi:10.1177/0022034513509281
PMCID: PMC3834658  PMID: 24132082
caries; periodontal disease; cohort study; alveolar bone loss; longitudinal study
25.  A Retrospective Study of Implant–Abutment Connections on Crestal Bone Level 
Journal of Dental Research  2013;92(12 Suppl):202S-207S.
This study compared the effects of external hex, internal octagon, and internal Morse taper implant–abutment connections on the peri-implant bone level before and after the occlusal loading of dental implants. Periapical radiographs of 103 implants (63 patients) placed between 2002 and 2010 were collected, digitized, standardized, and classified into groups based on the type of implant–abutment connection. These radiographs were then analyzed with image-processing software to measure the peri-implant crestal bone change during the healing phase (4 months after implant placement) and at loading phases 1 and 2 (3 and 6 months after occlusal loading, respectively). A generalized estimating equation method was employed for statistical analysis. The amount of peri-implant crestal bone change differed significantly among all time–phase pairs for all 3 types of implant–abutment connection, being greater in the healing phase than in loading phase 1 or 2. However, the peri-implant crestal bone change did not differ significantly among the 3 types of implant–abutment connections during the healing phase, loading phase 1, or loading phase 2. This retrospective clinical study reveals that the design of the implant–abutment connection appears to have no significant impact on short-term peri-implant crestal bone change.
doi:10.1177/0022034513510322
PMCID: PMC3860058  PMID: 24158343
internal octagon; internal Morse taper; peri-implant crestal bone change dental implant–abutment design; radiology; alveolar bone loss

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