TMEM119 (c.G143A, p.S48L) Mutation Is Involved in Primary Failure of Eruption by Attenuating Glycolysis-Mediated Osteogenesis.

Primary failure of eruption (PFE) is a rare oral disease with an incidence rate of 0.06%. It is characterized by abnormal eruption mechanisms that disrupt tooth eruption. The underlying pathogenic genetic variant and mechanism of PFE remain largely unknown. The purpose of this study was to explore the role of a novel transmembrane protein 119 (TMEM119) mutation in two PFE patients in a Chinese family. Information collection was performed on the family with a diagnosis of PFE, and blood samples from patients and healthy family members were extracted. Whole-exome sequencing was performed. Bioinformatics analysis revealed that a heterozygous variant in the TMEM119 gene (c.G143A, p.S48L) was a disease-associated mutation in this family. Recombinant pcDNA3.1 plasmid-containing wild-type and mutant TMEM119 expression cassettes were successfully constructed and transfected into MC3T3-E1 cells, respectively. The results of in vitro analysis suggested that the subcellular distribution of the TMEM119 protein was transferred from the cell cytoplasm to the nucleus, and the ability of cells to proliferate and migrate as well as glycolytic and mineralized capacities were reduced after mutation. Furthermore, rescue assays showed that activating transcription factor 4 (ATF4) overexpression rescued the attenuated glycolysis and mineralization ability of cells. Results of in vivo analysis demonstrated that TMEM119 was mainly expressed in the alveolar bone around the mouse molar germs, and the expression level increased with tooth eruption, demonstrated using immunohistochemistry and immunofluorescence. Collectively, the novel TMEM119 mutation is potentially pathogenic in the PFE family by affecting the glucose metabolism and mineralized function of osteoblasts, including interaction with ATF4. Our findings broaden the gene mutation spectrum of PFE and further elucidate the pathogenic mechanism of PFE.

Sex and ancestry patterning of residual correlations in human dental development: Cooperative genetic interaction and phenotypic plasticity.

OBJECTIVES: Most research in human dental age estimation has focused on point estimates of age, and most research on dental development theories has focused on morphology or eruption. Correlations between developing teeth using ordinal staging have received less attention. The effect of demographic variables on these correlations is unknown. I tested the effect of reference sample demographic variables on the residual correlation matrix using the lens of cooperative genetic interaction (CGI). MATERIALS AND METHODS: The sample consisted of Moorrees et al., Journal of Dental Research, 1963, 42, 1490-1502, scores of left mandibular permanent teeth from panoramic radiographs of 880 London children 3-22.99 years of age stratified by year of age, sex, and Bangladeshi or European ancestry. A multivariate cumulative probit model was fit to each sex/ancestry group (n = 220), each sex or ancestry (n = 440), and all individuals (n = 880). Residual correlation matrices from nine reference sample configurations were compared using Bartlett's tests of between-sample difference matrices against the identity matrix, hierarchical cluster analysis, and dendrogram cophenetic correlations. RESULTS: Bartlett's test results were inconclusive. Cluster analysis showed clustering by tooth class, position within class, and developmental timing. Clustering patterns and dendrogram correlations showed similarity by sex but not ancestry. DISCUSSION: Expectations of CGI were supported for developmental staging. This supports using CGI as a model for explaining patterns of variation within the dentition. Sex was found to produce consistent patterns of dental correlations, whereas ancestry did not. Clustering by timing of development supports phenotypic plasticity in the dentition and suggests shared environment over genetic ancestry to explain population differences.

[Analysis of amelogenesis imperfecta with abnormal tooth eruption caused by FAM83H mutation].

Objective: FAM83H is one of the major pathogenic genes of amelogenesis imperfecta (AI). Previous studies focused on the abnormal enamel development and mineralization caused by the mutations in FAM83H. Here we aimed to observe other effects of FAM83H mutations on tooth eruption besides AI through clinical case analysis. Methods: Published AI cases with FAM83H mutations were searched through PubMed database, and the characteristics of tooth eruption of each cases were counted and analyzed. The literature search range was from January 1, 2008 to February 28, 2023, using the keywords FAM83H and amelogenesis imperfecta. The included literature must provide the detailed radiographic imaging or dental eruption information of AI patients, as well as FAM83H gene mutation information. The basic clinical information, tooth phenotypes, and mutations of all the enrolled cases were collected and analyzed in order to find the characteristics of abnormal tooth eruption. Results: Among 45 papers about FAM83H related to AI, twenty meeting the inclusion criteria were selected, involving 50 AI patients carrying FAM83H mutations who had radiographic image data or the detailed description of tooth eruption. A total of 34 abnormal erupted teeth were from 12 patients (12/50, 24%), among which 85% (29/34) had clear eruption path without any eruption obstructions, either embedded (25/34, 74%) or partially erupted (4/34, 12%). Tooth position analysis found that abnormal eruption of canines and second molars accounted for the highest proportion, accounting for 38% (13/34) respectively. Conclusions: The mutations in FAM83H may lead to amelogenesis imperfecta as well as abnormal tooth eruption at specific tooth positions.

Identification of a novel PTH1R variant in a family with primary failure of eruption.

BACKGROUND: Primary failure of tooth eruption (PFE) is a rare autosome genetic disorder that causes open bite. This work aimed to report a small family of PFE(OMIM: # 125,350) with a novel PTH1R variant. One of the patients has a rare clinical phenotype of the anterior tooth involved only. CASE PRESENTATION: The proband was a 13-year-old young man with an incomplete eruption of the right upper anterior teeth, resulting in a significant open-bite. His left first molar partially erupted. Family history revealed that the proband's 12-year-old brother and father also had teeth eruption disorders. Genetic testing found a novel PTH1R variant (NM_000316.3 c.1325-1336del), which has never been reported before. The diagnosis of PFE was based on clinical and radiographic characteristics and the result of genetic testing. Bioinformatic analysis predicted this variant would result in the truncation of the G protein-coupled receptor encoded by the PTH1R, affecting its structure and function. CONCLUSION: A novel PTH1R variant identified through whole-exome sequencing further expands the mutation spectrum of PFE. Patients in this family have different phenotypes, which reflects the characteristics of variable phenotypic expression of PFE.

Genotype-phenotype analysis of selective failure of tooth eruption-A systematic review.

Tooth eruption is an important and unique biological process during craniofacial development. Both the genetic and environmental factors can interfere with this process. Here we aimed to find the failure pattern of tooth eruption among five genetic diseases. Both systematic review and meta-analysis were used to identify the genotype-phenotype associations of unerupted teeth. The meta-analysis was based on the characteristics of abnormal tooth eruption in 223 patients with the mutations in PTH1R, RUNX2, COL1A1/2, CLCN7, and FAM20A respectively. We found all the patients presented selective failure of tooth eruption (SFTE). Primary failure of eruption patients with PTH1R mutations showed primary or isolated SFTE1 in the first and second molars (59.3% and 52% respectively). RUNX2 related cleidocranial dysplasia usually had SFTE2 in canines and premolars, while COL1A1/2 related osteogenesis imperfecta mostly caused SFTE3 in the maxillary second molars (22.9%). In CLCN7 related osteopetrosis, the second molars and mandibular first molars were the most affected. While FAM20A related enamel renal syndrome most caused SFTE5 in the second molars (86.2%) and maxillary canines. In conclusion, the SFTE was the common characteristics of most genetic diseases with abnormal isolated or syndromic tooth eruption. The selective pattern of unerupted teeth was gene-dependent. Here we recommend SFTE to classify those genetic unerupted teeth and guide for precise molecular diagnosis and treatment.

Runx2 and Nell-1 in dental follicle progenitor cells regulate bone remodeling and tooth eruption.

Dental follicles are necessary for tooth eruption, surround the enamel organ and dental papilla, and regulate both the formation and resorption of alveolar bone. Dental follicle progenitor cells (DFPCs), which are stem cells found in dental follicles, differentiate into different kinds of cells that are necessary for tooth formation and eruption. Runt-related transcription factor 2 (Runx2) is a transcription factor that is essential for osteoblasts and osteoclasts differentiation, as well as bone remodeling. Mutation of Runx2 causing cleidocranial dysplasia negatively affects osteogenesis and the osteoclastic ability of dental follicles, resulting in tooth eruption difficulties. Among a variety of cells and molecules, Nel-like molecule type 1 (Nell-1) plays an important role in neural crest-derived tissues and is strongly expressed in dental follicles. Nell-1 was originally identified in pathologically fused and fusing sutures of patients with unilateral coronal synostosis, and it plays indispensable roles in bone remodeling, including roles in osteoblast differentiation, bone formation and regeneration, craniofacial skeleton development, and the differentiation of many kinds of stem cells. Runx2 was proven to directly target the Nell-1 gene and regulate its expression. These studies suggested that Runx2/Nell-1 axis may play an important role in the process of tooth eruption by affecting DFPCs. Studies on short and long regulatory noncoding RNAs have revealed the complexity of RNA-mediated regulation of gene expression at the posttranscriptional level. This ceRNA network participates in the regulation of Runx2 and Nell-1 gene expression in a complex way. However, non-study indicated the potential connection between Runx2 and Nell-1, and further researches are still needed.

A Novel lncRNA Mediates the Delayed Tooth Eruption of Cleidocranial Dysplasia.

Delayed eruption of permanent teeth is a common symptom of cleidocranial dysplasia (CCD). Previous studies have focused on the anomaly of osteogenesis resulting from mutations in the Runt-related transcription factor-2 gene (RUNX2). However, deficiencies in osteoclastogenesis and bone resorption, and the epigenetic regulation mediated by long non-coding (lnc)RNAs in CCD remain to be elucidated. Here, a novel osteoclast-specific lncRNA (OC-lncRNA) was identified during the osteoclast differentiation of RAW 264.7 cells transfected with a RUNX2 mutation expression cassette. We further confirmed that OC-lncRNA positively regulated osteoclastogenesis and bone resorption. The OC-lncRNA promoted the expression of CXC chemokine receptor type 3 (CXCR3) by competitively binding to microRNA (miR)-221-5p. The CXCR3-CXC-motif chemokine ligand 10 (CXCL10) interaction and nuclear factor-κB constituted a positive feedback that positively regulated osteoclastogenesis and bone resorption. These results demonstrate that OC-lncRNA-mediated osteoclast dysfunction via the OC-lncRNA-miR-221-5p-CXCR3 axis, which is involved in the process of delayed tooth eruption of CCD.

Single Nucleotide Polymorphisms in COX2 Is Associated with Persistent Primary Tooth and Delayed Permanent Tooth Eruption.

Persistent primary tooth (PPT) is a prevalent clinical condition that occurs when a primary tooth is over-retained beyond the established period of its normal exfoliation time, remaining in the oral cavity. Many factors could be involved in the risk of PPT; therefore, the aim of this study was to evaluate if single nucleotide polymorphisms (SNPs) in the COX2 gene are associated with PPT. Children undergoing orthodontic treatment were screened. Orthopantomographs were assessed to evaluate PPT according to the Nolla stage of its permanent successor. The primary tooth was considered retained when its successor permanent tooth was in Nolla stage 8 and below the alveolar crypt, Nolla stage 9, or Nolla stage 10. A saliva sample from each child was collected and used for DNA extraction. A real-time PCR of two SNPs, rs689466 (-1195 G/A) and rs5275 (+665 T/C), was performed. A chi-square test was used to compare the allele and genotype distribution. Haplotype analysis was also performed. A total of 100 children were included in the study. Fifty-one had at least one PPT, while 49 children were classified as a control. The number of teeth persistent in the oral cavity ranged from 1 to 8. The genotype distribution was associated with PPT in the co-dominant model (p = 0.006) for SNP rs5275. The individuals that carry two T alleles (TT) compared with the individuals that carry at least one C allele (C + TC) had an almost three times higher chance of presenting with PPT (p = 0.012; OR = 2.99, CI95% 1.28 to 6.95-recessive model). The haplotype C-A for the SNPs rs5275 and rs689466, respectively, was significantly associated (p = 0.042). In conclusion, single nucleotide polymorphisms in the gene encoding for COX2 are associated with persistent primary tooth and may delay permanent tooth eruption.

Development of dentition: From initiation to occlusion and related diseases.

BACKGROUND: The development of dentition begins in the embryonic oral cavity and progresses in the branchial arches and alveolar bone. Continuous cellular and molecular crosstalk occurs during crown formation, after which the tooth germ begins to migrate apically through the alveolar process into the oral cavity. It eventually comes in contact with its antagonist in the contralateral jaw to establish functional occlusion. Any defect in either step can result in delayed tooth development, the spectrum of which varies from a congenitally missing tooth to an impacted tooth (infraocclusion) with an eruption problem, both of which can impair oral function. HIGHLIGHT: Congenitally missing teeth or eruption problems may result from genetic mutations. Several different mutations have been identified, each causing a distinct phenotype. Thus, it is imperative that medical providers understand the fundamentals of these genetic principles that govern such dental diseases. CONCLUSION: In this review, we focus on several diseases, including congenitally missing teeth and tooth eruption problems. We review these diseases with aspect to their association with a particular syndrome, as well as independently in a non-syndromic capacity. We also review previously identified genetic mutations and discuss the possible mechanisms that cause individual phenotypes by analyzing previous investigations. We also discuss future prospects of how genetic diagnosis and precision medicine could impact the clinical environment in the field of dentistry. ETHICAL APPROVAL: Present study has been carried out in accordance with The Code of Ethics of the World Medical Association and approved by Institutional Review Board of Osaka University Graduate School of Dentistry.

Abnormal eruption of teeth in relation to FGFR1 heterozygote mutation: a rare case of osteoglophonic dysplasia with 4-year follow-up.

BACKGROUND: We report a case and its 4-year follow-up of Osteoglophonic dysplasia (OD), a rare disease that disturbs both skeletal and dental development, which is usually caused by heterozygous FGFR1 mutations. CASE PRESENTATION: This article presents a case where a 6-year-old male patient suffered dysregulation of tooth eruption and was diagnosed with osteogenic dysplasia from a fibroblast growth factor receptor 1 (FGFR1) heterozygote mutation. However, the number of teeth is within the normal range, and their roots are well developed. Several interventions were implemented with varying degrees of results. The details of the 4-year follow-up showed that the signs of OD were more pronounced, including dwarfism, frontal bossing, delayed skeletal maturation, anteverted nares, micrognathia, and prominent ears, but the patient's impacted teeth and edentulous jaws remained unchanged. CONCLUSIONS: FGFR1 heterozygote mutation and OD present significant difficulty for teeth eruption and subsequent intervention. Further measures ought to be taken in recognizing various symptoms presented by the patient. This case supports the significance of careful inquiry, comprehensive physical examination and correct diagnosis as indispensable steps for clinical practice in patients with unerupted teeth. Additionally, the detailed case and its 4-year follow-up length may provide new insights into osteogenic dysplasia and patients with impacted teeth while encouraging further exploration in treatment methods.

Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants.

BACKGROUND: Primary failure of eruption (PFE) is a hereditary condition, and linkage with variants in the PTH1R gene has been demonstrated in many cases. The clinical severity and expression of PFE is variable, and the genotype-phenotype correlation remains elusive. Further, the similarity between some eruption disorders that are not associated with PTH1R alterations is striking. To better understand the genotype-phenotype correlation, we examined the relationship between the eruption phenotype and PTH1R genotype in 44 patients with suspected PFE and 27 unaffected relatives. Sanger sequencing was employed to analyze carefully selected PFE patients. Potential pathogenicity of variants was evaluated against multiple genetic databases for function prediction and frequency information. RESULTS: Mutational analysis of the PTH1R coding sequence revealed 14 different variants in 38 individuals (30 patients and 8 first-degree relatives), 9 exonic and 5 intronic. Their pathogenicity has been reported and compared with the number and severity of clinical signs. In 72.7% of patients with pathogenic variants, five clinical and radiographic criteria have been found: involvement of posterior teeth, involvement of the distal teeth to the most mesial affected, supracrestal presentation, altered vertical growth of the alveolar process and posterior open-bite. In cases with mixed dentition (3), the deciduous molars of the affected quadrant were infraoccluded. DISCUSSION: The probability of an affected patient having a PTH1R variant is greater when five specific clinical characteristics are present. The likelihood of an eruption defect in the absence of specific clinical characteristics is rarely associated with a PTH1R mutation. CONCLUSIONS: We report here that systematic clinical and radiographic observation using a diagnostic rubric is highly valuable in confirming PFE and offers a reliable alternative for accurate diagnosis.

Vitamin D deficiency is a risk factor for delayed tooth eruption associated with persistent primary tooth.

OBJECTIVE: To verify the association between 25(OH)D level and polymorphisms in the vitamin D receptor gene (VDR) with the disturbance in the dental development and eruption. DESIGN: A total of 183 children from two datasets were evaluated. The first dataset was a case-control (15:15) designed to assess if persistent primary tooth (PPT) is associate with serum 25(OH)D level and with genetic polymorphisms in VDR. The second dataset of genomic DNA samples from 54 children with delayed tooth eruption (DTE) and 99 controls were analysed to verify if genetic polymorphisms in VDR (rs2228570 and rs739837) are associated with DTE. The 25(OH)D and the genotyping/allele distribution were analysed using the T-test and chi-square test, respectively. RESULTS: The level of 25(OH)D in the PPT group (24.9 ± 6.4 mg/mL) was significantly lower than the control (30.0 ± 7.0 mg/mL) (p=.047). Our data show that children with 25(OH)D deficiency are more likely to present PPT (OR = 2.36; 95%CI: 1.51, 3.70). The rs739837 and rs2228570 polymorphisms were not associated with DTE (OR = 1.44; 95%CI: 0.87, 2.39 and OR = 0.80; 95%CI: 0.45, 1.44, respectively). CONCLUSIONS: Vitamin D deficiency is a risk factor for PPT.

Lack of association between delayed tooth emergence and single nucleotide polymorphisms in estrogen receptors.

The purpose of the study was to investigate the association between single nucleotide polymorphisms (SNPs) in genes encoding estrogen receptors (ESR1 and ESR2, respectively) and delayed tooth emergence (DTE). This cross-sectional study was composed of biological unrelated children of both sexes, age ranging from 11 to 13 years old. DTE was defined when the successor primary tooth was still present in the oral cavity after its exfoliation time or the absence of the permanent tooth emergence into the oral cavity. Children were diagnosed with DTE when they had at least one delayed permanent tooth, according to age of exfoliation of each tooth proposed by The American Dental Association. Genomic DNA from saliva was used to evaluate the SNPs in ESR1 (rs9340799 and rs2234693) and ESR2 (rs1256049 and rs4986938) using Real-Time PCR. Chi-square or Fisher exact tests and Logistic Regression adjusted by age and gender were performed. SNP-SNP interaction was accessed by multifactor dimensionality reduction (MDR) analysis also adjusted by gender and age. The established alpha of this study was 5%. Among 537 included children, 296 (55%) were in the "DTE" group and the 241 (45%) were in the "Control" group. Age and gender were not statistically different among the groups (p>0.05). Genotype distribution of the SNPs rs9340799, rs2234693, rs1256049 and rs4986938 were not associated with DTE (p> 0.05). The models elected by MDR were not statistically significant either. Conclusions: The studied SNPs in ESR1 and ESR2 were not associated with permanent DTE.

A three-dimensional analysis of primary failure of eruption in humans and mice.

OBJECTIVES: Primary failure of eruption (PFE) is a genetic disorder exhibiting the cessation of tooth eruption. Loss-of-function mutations in parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH/PTHrP receptor, PPR) were reported as the underlying cause of this disorder in humans. We showed in a PFE mouse model that PTHrP-PPR signaling is responsible for normal dental follicle cell differentiation and tooth eruption. However, the mechanism underlying the eruption defect in PFE remains undefined. In this descriptive study, we aim to chronologically observe tooth eruption and root formation of mouse PFE molars through 3D microCT analyses. SETTING AND SAMPLE POPULATION: Two individuals with PFE were recruited at Showa University. A mouse PFE model was generated by deleting PPR specifically in PTHrP-expressing dental follicle and divided into three groups, PPRfl/fl ;R26RtdTomato/+ (Control), PTHrP-creER;PPRfl/+ ;R26RtdTomato/+ (cHet), and PTHrP-creER;PRRfl/fl ;R26RtdTomato/+ (cKO). MATERIALS AND METHODS: Images from human PFE subjects were acquired by CBCT. All groups of mouse samples were studied at postnatal days 14, 25, 91, and 182 after a tamoxifen pulse at P3, and superimposition of 3D microCT images among three groups was rendered. RESULTS: Mouse and human PFE molars exhibited a similar presentation in the 3D CT analyses. The quantitative analysis in mice demonstrated a statistically significant decrease in the eruption height of cKO first and second molars compared to other groups after postnatal day 25. Additionally, cKO molars demonstrated significantly shortened roots with dilacerations associated with the reduced interradicular bone height. CONCLUSIONS: Mouse PFE molars erupt at a much slower rate compared to normal molars, associated with shortened and dilacerated roots and defective interradicular bones.

Polymorphism in sequence of permanent tooth emergence in Czech children.

OBJECTIVES: The aim of the study is to determine norms of polymorphic variation in the sequence of permanent teeth in Czech children in order to establish first standards applicable to individuals. Setting out such standards, derived from the population to which they will be applied, are essential for diagnoses in paediatric dentistry, orthodontic treatment planning and for anthropological application. METHODS: Dental examinations were performed on a sample of 1,370 children (696 girls and 674 boys) aged 4-15 years. All emerged permanent teeth (other than third molars), when at least some part of crown has penetrated the oral mucosa, and the child's gender were recorded. The frequency of sequence polymorphism was calculated for each gender by counting instances of absent/present and present/absent across all possible intra-arch and inter-arch tooth pairs. RESULTS: Differential frequencies of polymorphic sequences were more common in the inter-arch tooth pairs than in the intra-arch pairs. The most similar frequencies in inter-arch pairs were observed in second mandibular premolar/second maxillary premolar in both genders. However, in the mandible there was a polymorphic sequence in the first molar/central incisor pair in both genders. Furthermore, mandibular polymorphisms were more commonly observed in the sequences of canine/second premolar in girls than in boys. Additionally, canine/second premolar polymorphic sequences were found to be more common in the maxilla in both genders. CONCLUSIONS: The data presented in this article are useful in the prediction of tooth emergence sequence in individual Czech children and are important in paediatric dentistry and in orthodontic treatment.

Breaking the rules: Phylogeny, not life history, explains dental eruption sequence in primates.

OBJECTIVES: Although a great deal is known about the biology of tooth development and eruption, there remains disagreement about the factors driving the evolution of dental eruption sequence. We assessed postcanine eruption sequence across a large sample of primates to test two hypotheses: (1) Dental eruption sequence is significantly correlated with life history and body size variables that capture postnatal growth and longevity (Schultz's Rule), and (2) Dental eruption sequence is conserved phylogenetically. MATERIALS AND METHODS: We assessed postcanine dental eruption sequence for 194 individuals representing 21 primate genera spanning eight families. With the inclusion of an additional 29 primate genera from the literature, this is the most comprehensive report on dental eruption sequence in primates to date. We used a series of phylogenetic analyses to statistically compare dental eruption sequence to life history and body size and test for phylogenetic signal in these traits. RESULTS: Dental eruption sequence is conserved phylogenetically in primates, and body and brain size are both significantly associated with dental eruption sequence. Ancestral state reconstruction supports the hypothesis that the third molar erupted before one or more of the premolars in the ancestor of primates and derived clades within primates evolved an eruption sequence in which the third molar erupts after the premolars. DISCUSSION: Schultz's Rule, as it is currently written and applied, is not supported by this extended data set. Our results demonstrate that dental eruption sequence is a far better predictor of phylogeny and will likely prove useful in phylogenetic hypotheses about relationships between extinct and extant mammalian taxa. The evolution of dental eruption sequence is likely driven by factors that significantly influence body size and mandibular symphyseal fusion.

Effect of Runx2 silencing on autophagy and RANKL expression in osteoblasts.

OBJECTIVE: This study aimed to investigate the effect of Runx2 silencing on autophagy and RANKL expression in mouse osteoblasts, and provide an experimental basis to assess obstacles in dental eruption. METHODS: In accordance with previously reported methods, LVpFU-GW-016PSC60109-1 virus was used to transfect mouse osteoblasts (MOI = 40). Target gene expression was assessed via cytometer, and the effect of silencing Runx2 was assessed via a two-step quantitative real-time polymerase chain reaction (qRT-PCR)-based method. Western blotting was performed to assess LC3, Beclin-1 and RANKL expression. RESULTS: As confirmed via qRT-PCR analysis, Runx2 was efficiently silenced in the experimental group (>90% efficiency). Western blotting revealed that LC3 and RANKL proteins were significantly down -regulated in the experimental group (group KD), their expression levels being particularly lower than those in the control group (group NC). However, Beclin-1 protein expression was not significantly different from that of the control. CONCLUSION: Upon Runx2 silencing, autophagy-related proteins and RANKL were repressed in osteoblasts, thereby potentially causing the tooth eruption disorder.

Gene expression profiles in dental follicles from patients with impacted canines.

Animal studies suggest that the dental follicle (DF) plays a major role in tooth eruption. However, the role of the DF during tooth impaction and related root resorptions in adjacent teeth is not clear. The hypothesis for the present study is that expression of regulatory factors involved in the bone remodelling process necessary for tooth eruption may differ between dental follicles from teeth with different clinical situations. We have analysed the gene expression profiles in the DF obtained from impacted canines, with (N = 3) or without (N = 5) signs of root resorption, and from control teeth (normal erupting teeth, mesiodens) (N = 3). DF from 11 patients (mean age: 13 years) obtains at the time of surgical exposure of the tooth. Due to the surgical time point, all teeth were in a late developmental stage. Gene expression related to osteoblast activation/bone formation, osteoclast recruitment and activation was analysed by RTqPCR. Genes related to bone formation (RUNX2, OSX, ALP, OCN, CX43) were highly expressed in all the samples, but osteoclast recruitment/activation markers (OPG, RANKL, MCP-1, CSF-1) were negligible. No apparent patterns or significant differences in gene expression were found between impacted canines, with or without signs of root resorption, or when compared to control teeth. Our results suggest the DF regulation of osteoclastic activity is limited in the late pre-emergent stage of tooth development, irrespective if the tooth is normally erupting or impacted. We suggest that the follicle may have an important regulatory function for alveolar bone formation in the final eruption process and CX43-gap junction communication could be an important signalling pathway.

Development of the gingival sulcus at the time of tooth eruption and the influence of genetic factors.

Tooth eruption is characterized by a concert of mechanisms that result in the emergence of teeth in the oral cavity. Genetic variants seem to regulate this process and the formation of a gingival sulcus around the teeth. Interindividual variability in the response to microbial triggers in the sulcus plays an important role in the onset and progression of periodontal diseases. Host genetic variants can influence this variability, affecting the response of the host to the subgingival biofilm. Genetic factors affecting tooth eruption could potentially influence susceptibility to periodontal diseases and, specifically, susceptibility to localized aggressive periodontitis. This review aims to discuss the evidence available for the role of host genetic variants in tooth eruption and to and to give some directions for prospective research in this topic.

The Sirt6 gene: Does it play a role in tooth development?

Dental Mesenchymal Cells (DMCs) are known to play a role in tooth development as well as in the repair and regeneration of dental tissue. A large number of signaling molecules regulate the proliferation and differentiation of DMC, though the underlying mechanisms are still not fully understood. Sirtuin-6 (SIRT6), a key regulator of aging, can exert an impact on embryonic stem cell (ESC) differentiation. The experimental deletion of Sirt6 in mouse bone marrow cells has been found to have an inhibiting impact on the bone mineral density and the osteogenic differentiation of these cells. The possible role of Sirt6 in tooth development, however, has at present remained largely unexplored. In the present study, we found that SIRT6 had no effect on tooth development before birth. However, Sirt6 gene deletion in knockout mice did have two post-natal impacts: a delay in tooth eruption and sluggishness in the development of dental roots. We propose an explanation of the possible molecular basis of the changes observed in Sirt6-/- mice. SIRT6 is expressed in mouse odontoblasts. Sirt6 deletion enhanced the proliferation of DMCs, as well as their capacity for adipogenic differentiation. On the other hand, it inhibited their capacity for in vitro osteogenic/chondrogenic differentiation. Further studies suggested that other factors may mediate the role of Sirt6 in odontogenesis. These include the nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (p38-MAPK), extracellular regulated MAP kinase (ERK) pathways and the mitochondrial energy. We demonstrated that Sirt6 plays a role in tooth root formation and confirmed that SIRT6 is necessary for DMC differentiation as well as for the development of the tooth root and for eventual tooth eruption. These results establish a new link between SIRT6 and tooth development.