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Organogenesis Dec 2022The development and repair of dentin are strictly regulated by hundreds of genes. Abnormal dentin development is directly caused by gene mutations and dysregulation....
The development and repair of dentin are strictly regulated by hundreds of genes. Abnormal dentin development is directly caused by gene mutations and dysregulation. Understanding and mastering this signal network is of great significance to the study of tooth development, tissue regeneration, aging, and repair and the treatment of dental diseases. It is necessary to understand the formation and repair mechanism of dentin in order to better treat the dentin lesions caused by various abnormal properties, whether it is to explore the reasons for the formation of dentin defects or to develop clinical drugs to strengthen the method of repairing dentin. Molecular biology of genes related to dentin development and repair are the most important basis for future research.
Topics: Dentin; Dentinogenesis; Odontoblasts; Odontogenesis
PubMed: 35023442
DOI: 10.1080/15476278.2021.2022373 -
Current Genomics Apr 2018During the last decades, a large amount of newly described microduplications and microdeletions associated with intellectual disability (ID) and related neuropsychiatric... (Review)
Review
During the last decades, a large amount of newly described microduplications and microdeletions associated with intellectual disability (ID) and related neuropsychiatric diseases have been discovered. However, due to natural limitations, a significant part of them has not been the focus of multidisciplinary approaches. Here, we address previously undescribed chromosome 4q21.2q21.3 microduplication for gene prioritization, evaluation of cognitive abilities and estimation of genomic mechanisms for brain dysfunction by molecular cytogenetic (cytogenomic) and gene expression (meta-) analyses as well as for neuropsychological assessment. We showed that duplication at 4q21.2q21.3 is associated with moderate ID, cognitive deficits, developmental delay, language impairment, memory and attention problems, facial dysmorphisms, congenital heart defect and dentinogenesis imperfecta. Gene-expression meta-analysis prioritized the following genes: ENOPH1, AFF1, DSPP, SPARCL1, and SPP1. Furthermore, genotype/phenotype correlations allowed the attribution of each gene gain to each phenotypic feature. Neuropsychological testing showed visual-perceptual and fine motor skill deficits, reduced attention span, deficits of the nominative function and problems in processing both visual and aural information. Finally, emerging approaches including molecular cytogenetic, bioinformatic (genome/epigenome meta-analysis) and neuropsychological methods are concluded to be required for comprehensive neurological, genetic and neuropsychological descriptions of new genomic rearrangements/diseases associated with ID.
PubMed: 29606904
DOI: 10.2174/1389202918666170717161426 -
Journal of Oral Biosciences Mar 2020The Bone Morphogenetic Proteins (BMPs) direct tooth development and still express in the adult tooth. We hypothesized that inhibition of BMP function would therefore...
OBJECTIVES
The Bone Morphogenetic Proteins (BMPs) direct tooth development and still express in the adult tooth. We hypothesized that inhibition of BMP function would therefore disrupt dentinogenesis by differentiated odontoblasts.
METHODS
We generated mice overexpressing the BMP-inhibitory protein Noggin in differentiated odontoblasts and osteocytes under control of a Dmp1 promoter-driven cre transgene. We compared the dentin phenotype in these mice with that in WT littermates and in mice with a Smad4 odontoblast/osteocyte knockout mediated by the same cre and therefore lacking all BMP and Tgfβ signaling in the same tissues.
RESULTS
Three-month-old first molars from both Noggin-expressing and Smad4-deleted mice showed decreased dentin volume with enlarged pulp cavities, and both displayed less organized and mineralized dentinal tubules compared to WT. The Smad4-ablated phenotype was more severe. While dentin sialophosphoprotein (DSPP) and bone sialoprotein (BSP) were decreased in the dentin of both lines, dentin matrix protein 1 (DMP1) was sharply increased in Noggin-expressing teeth.
CONCLUSIONS
The phenotypes we observed in Noggin-overexpressing and Smad4-conditional knockout teeth resemble the phenotype of Dentinogenesis Imperfecta (DGI) type III. Our results show that BMPs regulate post-natal dentinogenesis and that BMP-inhibitory proteins like Noggin play a role in that regulation. The increased severity of the Smad4 phenotype indicates that Tgfβ ligands, in addition to BMPs, play a crucial role in post-developmental dentinogenesis.
Topics: Animals; Carrier Proteins; Dentin; Dentinogenesis; Extracellular Matrix Proteins; Mice; Phosphoproteins; Sialoglycoproteins
PubMed: 31862386
DOI: 10.1016/j.job.2019.11.001 -
Dentistry Journal Apr 2023Collagen is the building block for the extracellular matrix in bone, teeth and other fibrous tissues. Osteogenesis imperfecta (OI), or brittle bone disease, is a... (Review)
Review
Collagen is the building block for the extracellular matrix in bone, teeth and other fibrous tissues. Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder that results from defective collagen synthesis or metabolism, resulting in bone fragility. The dental manifestation of OI is dentinogenesis imperfecta (DI), a genetic disorder that affects dentin structure and clinical appearance, with a characteristic feature of greyish-brown discolouration. The aim of this study was to conduct a systematic review to identify and/or define any ultrastructural changes in dentinal collagen in DI. Established databases were searched: Cochrane Library, OVID Embase, OVID Medline and PubMed/Medline. Search strategies included: Collagen Ultrastructure, DI and OI. Inclusion criteria were studies written in English, published after 1990, that examined human dental collagen of teeth affected by DI. A Cochrane data extraction form was modified and used for data collection. The final dataset included seventeen studies published from 1993 to 2021. The most prevalent findings on collagen in DI teeth were increased coarse collagen fibres and decreased fibre quantity. Additional findings included changes to fibre orientation (i.e., random to parallel) and differences to the fibre organisation (i.e., regular to irregular). Ultrastructural defects and anomalies included uncoiled collagen fibres and increased D-banding periodicity. Studies in collagen structure in DI reported changes to the surface topography, quantity, organisation and orientation of the fibres. Moreover, ultrastructural defects such as the packing/coiling and D-banding of the fibrils, as well as differences in the presence of other collagens are also noted. Taken together, this study provides an understanding of the changes in collagen and its impact on clinical translation, paving the way for innovative treatments in dental treatment.
PubMed: 37185473
DOI: 10.3390/dj11040095 -
Journal of Oral & Maxillofacial Research 2014Search in PubMed with keywords "enzymes, dentinogenesis, and dental caries" revealed only 4 items, but when combined with "enzymes, osteogenesis, and osteoporosis" as... (Review)
Review
OBJECTIVES
Search in PubMed with keywords "enzymes, dentinogenesis, and dental caries" revealed only 4 items, but when combined with "enzymes, osteogenesis, and osteoporosis" as high as 404 items resulted. Dental caries was associated with an order of magnitude fewer studies than the chronic bone disease, osteoporosis. This observation motivated this review.
MATERIAL AND METHODS
A comprehensive review of the available literature on role of enzymes in dentinogenesis and dental caries was undertaken using MEDLINE (PubMed) and Scopus. Keywords for the search were: enzymes and odontoblasts, enzymes and different forms of dentinogenesis as well as dental caries.
RESULTS
Search revealed studies which described odontoblasts harbouring numerous enzymes (hydrolases, including metalloproteinases, transaminases and dehydrogenases) during primary dentinogenesis. Alkaline phosphatase activity sharply decreased when odontoblasts turned into quiescent odontoblasts. Tertiary dentinogenesis was characterized first by reactionary dentine formation when alkaline phosphatase was highly reactivated. Then later some of these odontoblasts may die out and be replaced by other progenitor cells of pulpal origin. This tertiary dentine was called reparative dentine. Pulpal progenitor/stem cells revealed alkaline phosphatase activity in areas encircling inflamed pulp sections. Soft carious dentine revealed high hydrolase, transaminase and dehyrogenase activities that may have originated from invading microbes, saliva or were endogenous. Proteolytic activity was especially demonstrable using histochemical and biochemical means. Specifically, matrix metalloproteases may have originated partly from activated proenzymes of host origin.
CONCLUSIONS
Though dental studies are scanty when compared to bone, the active role of large spectrum of enzymes in healthy and carious dentine was given support.
PubMed: 25635210
DOI: 10.5037/jomr.2014.5403 -
Stem Cell Research & Therapy Jul 2023Dental pulp stem cells (DPSCs) play a crucial role in dentin-pulp complex regeneration. Further understanding of the mechanism by which DPSCs remain in a quiescent state...
BACKGROUND
Dental pulp stem cells (DPSCs) play a crucial role in dentin-pulp complex regeneration. Further understanding of the mechanism by which DPSCs remain in a quiescent state could contribute to improvements in the dentin-pulp complex and dentinogenesis.
METHODS
TSC1 conditional knockout (DMP1-Cre+; TSC1, hereafter CKO) mice were generated to increase the activity of mechanistic target of rapamycin complex 1 (mTORC1). H&E staining, immunofluorescence and micro-CT analysis were performed with these CKO mice and littermate controls. In vitro, exosomes were collected from the supernatants of MDPC23 cells with different levels of mTORC1 activity and then characterized by transmission electron microscopy and nanoparticle tracking analysis. DPSCs were cocultured with MDPC23 cells and MDPC23 cell-derived exosomes. Alizarin Red S staining, ALP staining, qRT‒PCR, western blotting analysis and micro-RNA sequencing were performed.
RESULTS
Our study showed that mTORC1 activation in odontoblasts resulted in thicker dentin and higher dentin volume/tooth volume of molars, and it increased the expression levels of the exosome markers CD63 and Alix. In vitro, when DPSCs were cocultured with MDPC23 cells, odontoblastic differentiation was inhibited. However, the inhibition of odontoblastic differentiation was reversed when DPSCs were cocultured with MDPC23 cells with mTORC1 overactivation. To further study the effects of mTORC1 on exosome release from odontoblasts, MDPC23 cells were treated with rapamycin or shRNA-TSC1 to inactivate or activate mTORC1, respectively. The results revealed that exosome release from odontoblasts was negatively correlated with mTORC1 activity. Moreover, exosomes derived from MDPC23 cells with active or inactive mTORC1 inhibited the odontoblastic differentiation of DPSCs at the same concentration. miRNA sequencing analysis of exosomes that were derived from shTSC1-transfected MDPC23 cells, rapamycin-treated MDPC23 cells or nontreated MDPC23 cells revealed that the majority of the miRNAs were similar among these groups. In addition, exosomes derived from odontoblasts inhibited the odontoblastic differentiation of DPSCs, and the inhibitory effect was positively correlated with exosome concentration.
CONCLUSION
mTORC1 regulates exosome release from odontoblasts to inhibit the odontoblastic differentiation of DPSCs, but it does not alter exosomal contents. These findings might provide a new understanding of dental pulp complex regeneration.
Topics: Mice; Animals; Odontoblasts; Extracellular Matrix Proteins; Dental Pulp; Exosomes; Cell Differentiation; Stem Cells; Cells, Cultured
PubMed: 37422687
DOI: 10.1186/s13287-023-03401-9 -
BioMed Research International 2022Portland cement (PC) is used in challenging endodontic situations in which preserving the health and functionality of pulp tissue is of considerable importance. PC forms... (Review)
Review
Portland cement (PC) is used in challenging endodontic situations in which preserving the health and functionality of pulp tissue is of considerable importance. PC forms the main component of mineral trioxide aggregate (MTA) and demonstrates similar desirable properties as an orthograde or retrograde filling material. PC is able to protect pulp against bacterial infiltration, induce reparative dentinogenesis, and form dentin bridge during the pulp healing process. The biocompatibility, bioactivity, and physical properties of PC have been investigated and in animal models, as well as in some limited clinical trials. This paper reviews Portland cement's structure and its characteristics and reaction in various environments and eventually accentuates the present concerns with this material. This bioactive endodontic cement has shown promising success rates compared to MTA; however, considerable modifications are required in order to improve its characteristics and expand its application scope as a root repair material. Hence, the extensive chemical modifications incorporated into PC composition to facilitate preparation and handling procedures are discussed. It is still important to further address the applicability, reliability, and cost-effectiveness of PC before transferring into day-to-day clinical practice.
Topics: Aluminum Compounds; Animals; Biocompatible Materials; Calcium Compounds; Dental Cements; Drug Combinations; Humans; Oxides; Root Canal Filling Materials; Silicates
PubMed: 35036431
DOI: 10.1155/2022/3314912 -
European Journal of Human Genetics :... Apr 2015Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular... (Review)
Review
Dentinogenesis imperfecta is an autosomal dominant disease characterized by severe hypomineralization of dentin and altered dentin structure. Dentin extra cellular matrix is composed of 90% of collagen type I and 10% of non-collagenous proteins among which dentin sialoprotein (DSP), dentin glycoprotein (DGP) and dentin phosphoprotein (DPP) are crucial in dentinogenesis. These proteins are encoded by a single gene: dentin sialophosphoprotein (DSPP) and undergo several post-translational modifications such as glycosylation and phosphorylation to contribute and to control mineralization. Human mutations of this DSPP gene are responsible for three isolated dentinal diseases classified by Shield in 1973: type II and III dentinogenesis imperfecta and type II dentin dysplasia. Shield classification was based on clinical phenotypes observed in patient. Genetics results show now that these three diseases are a severity variation of the same pathology. So this review aims to revise and to propose a new classification of the isolated forms of DI to simplify diagnosis for practitioners.
Topics: Collagen Type I; Dentin; Dentin Dysplasia; Dentinogenesis Imperfecta; Extracellular Matrix Proteins; Genetic Variation; Humans; Mutation; Phenotype; Phosphoproteins; Sialoglycoproteins
PubMed: 25118030
DOI: 10.1038/ejhg.2014.159 -
Frontiers in Cell and Developmental... 2021Embryonic development and stem cell differentiation are orchestrated by changes in sequential binding of regulatory transcriptional factors to their motifs. These...
Embryonic development and stem cell differentiation are orchestrated by changes in sequential binding of regulatory transcriptional factors to their motifs. These processes are invariably accompanied by the alternations in chromatin accessibility, conformation, and histone modification. Odontoblast lineage originates from cranial neural crest cells and is crucial in dentinogenesis. Our previous work revealed several transcription factors (TFs) that promote odontoblast differentiation. However, it remains elusive as to whether chromatin accessibility affects odontoblast terminal differentiation. Herein, integration of single-cell RNA-seq and bulk RNA-seq revealed that odontoblast differentiation using dental papilla cells at E18.5 was comparable to the crown odontoblast differentiation trajectory of OC (osteocalcin)-positive odontogenic lineage. Before odontoblast differentiation, ATAC-seq and H3K27Ac CUT and Tag experiments demonstrated high accessibility of chromatin regions adjacent to genes associated with odontogenic potential. However, following odontoblastic induction, regions near mineralization-related genes became accessible. Integration of RNA-seq and ATAC-seq results further revealed that the expression levels of these genes were correlated with the accessibility of nearby chromatin. Time-course ATAC-seq experiments further demonstrated that odontoblast terminal differentiation was correlated with the occupation of the basic region/leucine zipper motif (bZIP) TF family, whereby we validated the positive role of ATF5 . Collectively, this study reports a global mapping of open chromatin regulatory elements during dentinogenesis and illustrates how these regions are regulated via dynamic binding of different TF families, resulting in odontoblast terminal differentiation. The findings also shed light on understanding the genetic regulation of dentin regeneration using dental mesenchymal stem cells.
PubMed: 34901015
DOI: 10.3389/fcell.2021.769193 -
Global Medical Genetics Sep 2021Dentin sialophosphoprotein ( ) gene mutations cause autosomal dominantly inherited diseases. gene mutations lead to abnormal expression of DSPP, resulting in a series... (Review)
Review
Dentin sialophosphoprotein ( ) gene mutations cause autosomal dominantly inherited diseases. gene mutations lead to abnormal expression of DSPP, resulting in a series of histological, morphological, and clinical abnormalities. A large number of previous studies demonstrated that DSPP is a dentinal-specific protein, and gene mutations lead to dentin dysplasia and dentinogenesis imperfecta. Recent studies have found that DSPP is also expressed in bone, periodontal tissues, and salivary glands. DSPP is involved in the formation of the periodontium as well as tooth structures. DSPP deficient mice present furcation involvement, cementum, and alveolar bone defect. We speculate that similar periodontal damage may occur in patients with mutations. This article reviewed the effects of gene mutations on periodontal status. However, almost all of the research is about animal study, there is no evidence that mutations cause periodontium defects in patients yet. We need to conduct systematic clinical studies on mutation families in the future to elucidate the effect of gene on human periodontium.
PubMed: 34430959
DOI: 10.1055/s-0041-1726416