Secular changes in dental development of Korean children aged 4 to 16 years over a 10-year period.

This study evaluated 10-year secular changes in dental maturity and dental development among Korean children. A retrospective analysis of panoramic radiograph samples from Korean children (4-16 years old) taken in 2010 and 2020 was conducted. The 2010 group consisted of 3491 radiographs (1970 boys and 1521 girls), and the 2020 group included 5133 radiographs (2825 boys and 2308 girls). Using Demirjian's method, dental maturity scores and dental developmental stages were assessed. For intra-observer reliability, Weighted Cohen's kappa was used, and Mann-Whitney U tests were performed to compare the 2020 and 2010 groups. A slight acceleration in dental maturity was observed in both boys and girls, with the difference being more noticeable in boys at an earlier age. Statistically significant differences were noted at ages 4, 5 and 7 for boys, and at age 6 for girls. Despite these differences, the individual dental development stages of 2020 and 2010 showed inconsistent trends with limited differences. Generally, girls demonstrate more advanced dental maturity than boys. A slight acceleration in Korean children's dental maturity was observed over a 10-year period when comparing the 2020 groups to the 2010 groups.

Radiological Evaluation of the Accuracy of Demirjian, Nolla, and Willems Methods for Dental Age Estimation in 3-17-Year-Old Iranian Children.

Background: The stage of tooth formation is one of the most reliable indicators for predicting a patient's developmental age by radiographs. This study compared the accuracy of three distinct dental age estimation methods (Demirjian, Nolla, and Willems) in children aged 3-17 in the northern Iranian population. Methods: This cross-sectional study examined panoramic radiographs of 434 children aged 3-17 from Mazandaran Province, Iran, who had teeth 31-37 present on the left mandible. This study employed the Demirjian, Nolla, and Willems methods to estimate the dental age of the sample and compare it with the chronological age. The data were analyzed using SPSS v16. A paired t-test was used to compare chronological and dental ages. The Pearson correlation was used to correlate the chronological and dental ages. The errors of different methods were compared using the Wilcoxon test. P values < 0.05 were considered significant for all tests except Wilcoxon. For Wilcoxon, a P value < 0.017 was considered significant. Results: The three methods presented differing mean estimated ages. The Demirjian method delivered the highest mean, and all three methods differed significantly when compared in pairs. The results showed that the Demirjian method overestimated chronological age by 0.25 years (P < 0.001) in girls and 0.09 years (P = 0.28) in boys. The Willems method underestimated chronological age by 0.05 years (P = 0.47) in girls and 0.12 years (P = 0.13) in boys. The Nolla method underestimated chronological age by 0.41 years (P < 0.001) in girls and 0.40 years (P < 0.001) in boys. The accuracy of each method varied with the patient's age. Conclusion: According to the findings, the Willems method outperformed the Demirjian method, and the Demirjian method exceeded the Nolla method for estimating dental age in Iranian children aged 3-17. Overall, the Demirjian method overestimated the age of the study population, whereas the other two underestimated it.

The effect of birth weight on tooth development by Demirjian's method.

OBJECTIVES: The aim of this study was to investigate the impact of birth weight on tooth development in children aged 7-8 years. MATERIALS AND METHODS: This retrospective cohort study comprised 75 children born at Bint Al-Huda Hospital, Bojnurd, in 2013-2014. The children were categorized into three groups based on their birth weight: Normal Birth Weight (NBW), Low Birth Weight (LBW), and Very Low Birth Weight (VLBW). Panoramic radiographs were taken for orthodontic examination, and Demirjian's 8-teeth method was employed to determine dental age. The study compared dental and chronological age within each group. Data analysis utilized SPSS software version 26, employing One-way ANOVA and chi-square tests. Statistical significance was set at P ≤ 0.05. RESULTS: The mean difference in dental and chronological age for Very Low Birth Weight (VLBW) children was 0.22 ± 0.44 years, for Low Birth Weight (LBW) children it was 0.19 ± 0.45 years, and for Normal Birth Weight (NBW) children, it was 0.08 ± 0.46 years. Although the mean difference decreased with increasing birth weight, this trend did not achieve statistical significance (P = 0.55). Furthermore, no significant differences were observed between the weight groups (P = 0.529) or genders (P = 0.191).

Reading children's teeth to reconstruct life history and the evolution of human cooperation and cognition: The role of dental enamel microstructure and chemistry.

Studying infants in the past is crucial for understanding the evolution of human life history and the evolution of cooperation, cognition, and communication. An infant's growth, health, and mortality can provide information about the dynamics and structure of a population, their cultural practices, and the adaptive capacity of a community. Skeletal remains provide one way of accessing this information for humans recovered prior to the historical periods. Teeth in particular, are retrospective archives of information that can be accessed through morphological, micromorphological, and biogeochemical methods. This review discusses how the microanatomy and formation of teeth, and particularly enamel, serve as archives of somatic growth, stress, and the environment. Examining their role in the broader context of human evolution, we discuss dental biogeochemistry and emphasize how the incremental growth of tooth microstructure facilitates the reconstruction of temporal data related to health, diet, mobility, and stress in past societies. The review concludes by considering tooth microstructure as a biomarker and the potential clinical applications.

Dental Age Estimation in Northern Chinese Han Children and Adolescents Using Demirjian's Method Combined with Machine Learning Algorithms.

OBJECTIVES: To investigate the application value of combining the Demirjian's method with machine learning algorithms for dental age estimation in northern Chinese Han children and adolescents. METHODS: Oral panoramic images of 10 256 Han individuals aged 5 to 24 years in northern China were collected. The development of eight permanent teeth in the left mandibular was classified into different stages using the Demirjian's method. Various machine learning algorithms, including support vector regression (SVR), gradient boosting regression (GBR), linear regression (LR), random forest regression (RFR), and decision tree regression (DTR) were employed. Age estimation models were constructed based on total, female, and male samples respectively using these algorithms. The fitting performance of different machine learning algorithms in these three groups was evaluated. RESULTS: SVR demonstrated superior estimation efficiency among all machine learning models in both total and female samples, while GBR showed the best performance in male samples. The mean absolute error (MAE) of the optimal age estimation model was 1.246 3, 1.281 8 and 1.153 8 years in the total, female and male samples, respectively. The optimal age estimation model exhibited varying levels of accuracy across different age ranges, which provided relatively accurate age estimations in individuals under 18 years old. CONCLUSIONS: The machine learning model developed in this study exhibits good age estimation efficiency in northern Chinese Han children and adolescents. However, its performance is not ideal when applied to adult population. To improve the accuracy in age estimation, the other variables can be considered.

Bioinformatics for Dentistry: A secondary database for the genetics of tooth development.

Genes strictly regulate the development of teeth and their surrounding oral structures. Alteration of gene regulation leads to tooth disorders and developmental anomalies in tooth, oral, and facial regions. With the advancement of gene sequencing technology, genomic data is rapidly increasing. However, the large sets of genomic and proteomic data related to tooth development and dental disorders are currently dispersed in many primary databases and literature, making it difficult for users to navigate, extract, study, or analyze. We have curated the scattered genetic data on tooth development and created a knowledgebase called 'Bioinformatics for Dentistry' (https://dentalbioinformatics.com/). This database compiles genomic and proteomic data on human tooth development and developmental anomalies and organizes them according to their roles in different stages of tooth development. The database is built by systemically curating relevant data from the National Library of Medicine (NCBI) GenBank, OMIM: Online Mendelian Inheritance in Man, AlphaFold Protein Structure Database, Reactome pathway knowledgebase, Wiki Pathways, and PubMed. The accuracy of the included data was verified from supporting primary literature. Upon data curation and validation, a simple, easy-to-navigate browser interface was created on WordPress version 6.3.2, with PHP version 8.0. The website is hosted in a cloud hosting service to provide fast and reliable data transfer rate. Plugins are used to ensure the browser's compatibility across different devices. Bioinformatics for Dentistry contains four embedded filters for complex and specific searches and free-text search options for quick and simple searching through the datasets. Bioinformatics for Dentistry is made freely available worldwide, with the hope that this knowledgebase will improve our understanding of the complex genetic regulation of tooth development and will open doors to research initiatives and discoveries. This database will be expanded in the future by incorporating resources and built-in sequence analysis tools, and it will be maintained and updated annually.

Myosin II mediates Shh signals to shape dental epithelia via control of cell adhesion and movement.

The development of ectodermal organs begins with the formation of a stratified epithelial placode that progressively invaginates into the underlying mesenchyme as the organ takes its shape. Signaling by secreted molecules is critical for epithelial morphogenesis, but how that information leads to cell rearrangement and tissue shape changes remains an open question. Using the mouse dentition as a model, we first establish that non-muscle myosin II is essential for dental epithelial invagination and show that it functions by promoting cell-cell adhesion and persistent convergent cell movements in the suprabasal layer. Shh signaling controls these processes by inducing myosin II activation via AKT. Pharmacological induction of AKT and myosin II can also rescue defects caused by the inhibition of Shh. Together, our results support a model in which the Shh signal is transmitted through myosin II to power effective cellular rearrangement for proper dental epithelial invagination.

Research Progress on Dental Age Estimation Based on MRI Technology.

Dental age estimation is a crucial aspect and one of the ways to accomplish forensic age estimation, and imaging technology is an important technique for dental age estimation. In recent years, some studies have preliminarily confirmed the feasibility of magnetic resonance imaging (MRI) in evaluating dental development, providing a new perspective and possibility for the evaluation of dental development, suggesting that MRI is expected to be a safer and more accurate tool for dental age estimation. However, further research is essential to verify its accuracy and feasibility. This article reviews the current state, challenges and limitations of MRI in dental development and age estimation, offering reference for the research of dental age assessment based on MRI technology.

Roles of the histone methyltransferase SET domain bifurcated 1 in epithelial cells during tooth development.

OBJECTIVE: This study aimed to reveal the effects of SET domain bifurcated 1 (SETDB1) on epithelial cells during tooth development. DESIGN: We generated conditional knockout mice (Setdb1fl/fl,Keratin14-Cre+ mice), in which Setdb1 was deleted only in epithelial cells. At embryonic day 14.5 (E14.5), immunofluorescence staining was performed to confirm the absence of SETDB1 within the epithelium of tooth embryos from Setdb1fl/fl,Keratin14-Cre+ mice. Mouse embryos were harvested after reaching embryonic day 13.5 (E13.5), and sections were prepared for histological analysis. To observe tooth morphology in detail, electron microscopy and micro-CT analysis were performed at postnatal months 1 (P1M) and 6 (P6M). Tooth embryos were harvested from postnatal day 7 (P7) mice, and the epithelial components of the tooth embryos were isolated and examined using quantitative RT-PCR for the expression of genes involved in tooth development. RESULTS: Setdb1fl/fl,Keratin14-Cre+ mice exhibited enamel hypoplasia, brittle and fragile dentition, and significant abrasion. Coronal sections displayed abnormal ameloblast development, including immature polarization, and a thin enamel layer that detached from the dentinoenamel junction at P7. Electron microscopic analysis revealed characteristic findings such as an uneven surface and the absence of an enamel prism. The expression of Msx2, Amelogenin (Amelx), Ameloblastin (Ambn), and Enamelin (Enam) was significantly downregulated in the epithelial components of tooth germs in Setdb1fl/fl,Keratin14-Cre+ mice. CONCLUSIONS: These results indicate that SETDB1 in epithelial cells is important for tooth development and clarify the relationship between the epigenetic regulation of SETDB1 and amelogenesis imperfecta for the first time.

[Theory and practice of mesenchymal condensation directing tooth development and regeneration].

Mesenchymal stem cells, under spatiotemporal regulation of genes and microenvironment, are capable of spontaneously aggregating into dense regions, a phenomenon known as mesenchymal condensation. Mesenchymal condensation is an evolutionarily conserved developmental event that is critical in initiating morphogenesis of teeth and systemic organs. Mesenchymal stem cells hold the intrinsic ability to self-assemble in culture, and the generation of stem cell aggregates based on this property that mimics developmental mesenchymal condensation has become a potent and promising approach in regenerative medicine. This review discusses the mesenchymal condensation principles and its role as well as mechanism in tooth morphogenesis, as well as the engineering strategies for constructing mesenchymal stem cell aggregates and their application experience in tooth regeneration. It aims to start from the perspective of "development-inspired regeneration" and provide insights into understanding stem cell developmental biology and establishing new organ regenerative strategies.

[Role of Fibroblast Growth Factor 7 in Craniomaxillofacial Development]. / æˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­7åœ¨é¢ é¢Œé¢å‘è‚²ä¸­çš„ä½œç”¨.

Craniomaxillofacial development involves a series of highly ordered temporal-spatial cellular differentiation processes in which a variety of cell signaling factors, such as fibroblast growth factors, play important regulatory roles. As a classic fibroblast growth factor, fibroblast growth factor 7 (FGF7) serves a wide range of regulatory functions. Previous studies have demonstrated that FGF7 regulates the proliferation and migration of epithelial cells, protects them, and promotes their repair. Furthermore, recent findings indicate that epithelial cells are not the only ones subjected to the broad and powerful regulatory capacity of FGF7. It has potential effects on skeletal system development as well. In addition, FGF7 plays an important role in the development of craniomaxillofacial organs, such as the palate, the eyes, and the teeth. Nonetheless, the role of FGF7 in oral craniomaxillofacial development needs to be further elucidated. In this paper, we summarized the published research on the role of FGF7 in oral craniomaxillofacial development to demonstrate the overall understanding of FGF7 and its potential functions in oral craniomaxillofacial development.

Lead exposure across the life course and age at death.

BACKGROUND: Lead (Pb) exposure has been associated with an increased risk of all-cause mortality, even at low levels. Little is known about how the timing of Pb exposure throughout life may influence these relationships. Quantifying the amount of Pb present in various tissues of the body provides measurements of exposure from different periods of life. These include bone, tooth enamel, which is the hard outer layer of the crown, and tooth cementum, which is the calcified connective tissue covering the tooth root. The purpose of the study was to examine Pb exposure at multiple periods throughout life, including childhood (enamel), adulthood (cementum), and later life (bone), and to estimate their associations with age at death. METHODS: 208 skeleton donors (born 1910-1960) from an ongoing case-control study were included in this study. Pb was measured in tibia (shin), bone using X-Ray Florescence and in teeth using Laser-Ablation Inductively Coupled Plasma Mass Spectroscopy. After excluding unusually high measurements (>2sd), this resulted in a final sample of 111 with all exposure measures. Correlations across measures were determined using partial Spearman correlations. Associations between Pb exposure and age at death were estimated using Multivariable Linear Regression. RESULTS: Pb measures across exposure periods were all significantly correlated, with the highest correlation between cementum and tibia measures (r = 0.61). Donors were largely female (63.0 %), White (97.3 %), and attended some college (49.5 %). Single exposure models found that higher tooth cementum Pb (-1.27; 95 % CI: -2.48, -0.06) and tibia bone Pb (-0.91; 95 % CI: -1.67, -0.15) were significantly associated with an earlier age at death. When considered simultaneously, only cementum Pb remained significant (-1.51; 95 % CI: -2.92, -0.11). Secondary analyses suggest that the outer cementum Pb may be especially associated with an earlier age at death. CONCLUSION: Results suggest that higher Pb exposure is associated with an earlier age at death, with adulthood as the life period of most relevance. Additional studies using Pb exposure measures from different life stages should be conducted.

Artificial neural networks reconstruct missing perikymata in worn teeth.

Dental evolutionary studies in hominins are key to understanding how our ancestors and close fossil relatives grew from the early stages of embryogenesis into adults. In a sense, teeth are like an airplane's 'black box' as they record important variables for assessing developmental timing, enabling comparisons within and between populations, species, and genera. The ability to discern this type of nuanced information is embedded in the nature of how tooth enamel and dentin form: incrementally and over years. This incremental growth leaves chronological indicators in the histological structure of enamel, visible on the crown surface as perikymata. These structures are used in the process of reconstructing the rate and timing of tooth formation. Unfortunately, the developmentally earliest growth lines in lateral enamel are quickly lost to wear once the tooth crown erupts. We developed a method to reconstruct these earliest, missing perilymata from worn teeth through knowledge of the later-developed, visible perikymata for all tooth types (incisors, canines, premolars, and molars) using a modern human dataset. Building on our previous research using polynomial regressions, here we describe an artificial neural networks (ANN) method. This new ANN method mostly predicts within 2 counts the number of perikymata present in each of the first three deciles of the crown height for all tooth types. Our ANN method for estimating perikymata lost through wear has two immediate benefits: more accurate values can be produced and worn teeth can be included in dental research. This tool is available on the open-source platform R within the package teethR released under GPL v3.0 license, enabling other researchers the opportunity to expand their datasets for studies of periodicity in histological growth, dental development, and evolution.

From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration.

Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage - both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field - and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine.

Technical note: RP Atlas-an unprecedented proposal for a Brazilian population dental development chart based on the London atlas.

Age estimation methods through developmental atlases are simplified by image comparison using radiographs. Atlas-based methods have been utilized to create population-specific charts addressing population diversity. To tackle the absence of a dedicated atlas for the Brazilian population, the objective of the present study was to create a new atlas for dental development in Brazil based on the London Atlas chart. The new atlas (RP Atlas) is based on the median of tooth development, eruption, and resorption in individuals aged 5 to 23. The sample (567 individuals) was divided between females (n = 290) and males (n = 277). The RP Atlas was handcrafted, scanned, colored, and clustered in two atlases divided by sex. The development of a specific atlas for the Brazilian population has the potential to enhance the accuracy of age estimation in forensic scenarios, notably in a mixed country like Brazil. Further research is needed to assess the suitability of the newly developed atlas for the Brazilian population.

Dental age estimation methods applied to Indian children and adolescents: A systematic review and meta-analysis.

Country-specific systematic reviews and meta-analyses have been proposed to compile the available literature and rank methods based on their performance for a target population. India is a country with a vast scientific literature on dental age estimation. This systematic review aimed to provide evidence to help the decision of experts regarding the method of choice for dental age estimation in India. The research protocol was registered in Open Science Framework. Literature Search was performed in Embase, LILACS, MedLine (via PubMed), SciELO, Scopus and Web of Science. Grey Literature was searched in Google Scholar and ProQuest. Observational cross-sectional studies that compared chronological and estimated ages using Demirjian (original [DEM] and Chaillet's modification [modified-DEM]) and Acharya (ACH) methods were included. JBI tool was used to assess the risk of bias. The search detected 9799 studies, out of which 56 were eligible (n=13,107 panoramic radiographs of Indian individuals). Low risk of bias was registered for 48 studies, while 8 presented a moderate risk of bias. The meta-analysis showed a standardized mean difference between chronological and estimated ages of -0.11 (95%CI: -0.29; 0.07), 0.74 (95%CI: 0.39; 1.09), and -0.01 (95%CI: -0.23; 0.22) years for DEM, modified-DEM and ACH, respectively. High heterogeneity (I2=88-93%) was observed across studies for all the methods, including subgroup analyses based on sex. This study ranked ACH, DEM and modified-DEM (from the best to the worse) performances in the Indian population.

The role of O-GlcNAcylation mediated by OGT during tooth development.

To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O-GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O-GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage-specific immunostaining results against O-GlcNAc and O-GlcNAc transferase (OGT) in developing tooth germs would suggest that O-GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT-mediated O-GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI-1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI-1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real-time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of ß-catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT-inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT-mediated O-GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis.

Tiempo empleado para estimar edad dental en niños peruanos comparando el método de Demirjian y el cuadro integral del enfoque de Demirjian: un estudio piloto / Time spent to estimate dental age in peruvian children comparing the demirjian method and the comprehensive chart based on demirjian method: a pilot study

El objetivo de este estudio fue comparar el tiempo empleado al estimar la edad dental (ED) entre el método propuesto por Demirjian et al. y el cuadro integral del enfoque de Demirjian (DAEcc) utilizando radiografías panorámicas digitales de individuos peruanos de 5 a 13 años residentes en Lima. Se realizó un estudio no experimental, comparativo, transversal y retrospectivo. Se utilizaron 100 radiografías panorámicas digitales que presentaban siete dientes permanentes mandibulares izquierdos. Una odontóloga forense capacitada y calibrada determinó el tiempo utilizado en evaluar la maduración dental y la estimación de ED con dos métodos (Demirjian y DAEcc). La unidad de medida utilizada fue los minutos (min.). No hubo diferencias en el tiempo de evaluación del estadio de maduración dental entre ambos métodos (p<0,05). El tiempo para estimar ED fue estadísticamente inferior con DAEcc (2,09 min) que con Demirjian (4,19 min). La diferencia del tiempo total de evaluación resultó estadísticamente significativa entre ambos métodos (Δ2,1 min.; 2,05-2,11; p=0,000). La aplicación del DAEcc redujo en 50 % el tiempo empleado en estimar ED en comparación con los cuadros propuestos por Demirjian. Aunque la odontología forense se centra en el estudio de la eficacia de estimación de la edad, es necesario abordar también su uso práctico.

SUMMARY: The objective of this study was to compare the time used to estimate dental age (DA) between the method proposed by Demirjian et al., and the comprehensive chart for dental age estimation (DAEcc) using digital panoramic radiographs of Peruvian individuals aged 5 to 13 years residing in Lima. A non- experimental, comparative, cross-sectional and retrospective study was carried out. 100 digital panoramic radiographs showing seven mandibular left permanent teeth were used. A trained and calibrated forensic odontologist determined the time used to assess tooth maturation and DA estimation with two methods (Demirjian and DAEcc). The unit of measurement used was minutes (min.). There were no differences in the evaluation time of the dental maturation stage between both methods (p<0.05). The time spent to estimate DA was statistically less with DAEcc (2.09 min) than with Demirjian (4.19 min). The difference in total evaluation time was statistically significant between both methods (Δ2.1 min; 2.05-2.11; p=0.000).The application of DAEcc reduced by 50 % the time spent estimating DA compared to the method proposed by Demirjian. Although forensic odontology focuses on the study of the effectiveness of age estimation, its practical use needs to be addressed as well.

Effects of anti-RANKL antibodies administered to pregnant mice on bone and tooth development in neonates.

OBJECTIVES: This study examined how the anti-bone resorptive agent denosumab, which comprises anti-receptor activator of nuclear factor kappa B ligand (anti-RANKL) monoclonal antibodies, administered during pregnancy affected neonatal development. Anti-RANKL antibodies, which are known to bind to mouse RANKL and inhibit osteoclast formation, were administered to pregnant mice. Following this, the survival, growth, bone mineralization, and tooth development of their neonates were analyzed. METHODS: Anti-RANKL antibodies (5 mg/kg) were injected into pregnant mice on day 17 of gestation. After parturition, their neonatal offspring underwent microcomputed tomography at 24 h and at 2, 4, and 6 weeks after birth. Three-dimensional bone and teeth images were subjected to histological analysis. RESULTS: Approximately 70% of the neonatal mice born to mice who received anti-RANKL antibodies died within 6 weeks after birth. These mice had a significantly lower body weight and significantly higher bone mass compared with the control group. Furthermore, delayed tooth eruption and abnormal tooth morphology (eruption length, enamel surface, and cusps) were observed. Conversely, while the tooth germ shape and mothers against decapentaplegic homolog 1/5/8 expression remained unchanged at 24 h after birth in the neonatal mice born to mice that received anti-RANKL antibodies, osteoclasts were not formed. CONCLUSIONS: These results suggest that anti-RANKL antibodies administered to mice in the late stage of pregnancy results in adverse events in their neonatal offspring. Thus, it is speculated that administering denosumab to pregnant humans will affect fetal development and growth after birth.

Mesenchymal condensation in tooth development and regeneration: a focus on translational aspects of organogenesis.

The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.