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Research Square Sep 2023BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of...
BMP2 signaling plays a pivotal role in odontoblast differentiation and maturation during odontogenesis. Teeth lacking Bmp2 exhibit a morphology reminiscent of dentinogenesis imperfecta (DGI), associated with mutations in dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) genes. Mechanisms by which BMP2 signaling influences expressions of DSPP and DMP1 and contributes to DGI remain elusive. To study the roles of BMP2 in dentin development, we generated Bmp2 conditional knockout (cKO) mice. Through a comprehensive approach involving RNA-seq, immunohistochemistry, promoter activity, ChIP, and Re-ChIP, we investigated downstream targets of Bmp2. Notably, the absence of Bmp2 in cKO mice led to dentin insufficiency akin to DGI. Disrupted Bmp2 signaling was linked to decreased expression of Dspp and Dmp1, as well as alterations in intracellular translocation of transcription factors Dlx3 and Sp7. Intriguingly, upregulation of Dlx3, Dmp1, Dspp, and Sp7, driven by BMP2, fostered differentiation of dental mesenchymal cells and biomineralization. Mechanistically, BMP2 induced phosphorylation of Dlx3, Sp7, and histone acetyltransferase GCN5 at Thr and Tyr residues, mediated by Akt and Erk kinases. This phosphorylation facilitated protein nuclear translocation, promoting interactions between Sp7 and Dlx3, as well as with GCN5 on Dspp and Dmp1 promoters. The synergy between Dlx3 and Sp7 bolstered transcription of Dspp and Dmp1. Notably, BMP2-driven GCN5 acetylated Sp7 and histone H3, while also recruiting RNA polymerase II to Dmp1 and Dspp chromatins, enhancing their transcriptions. Intriguingly, BMP2 suppressed the expression of histone deacetylases. we unveil hitherto uncharted involvement of BMP2 in dental cell differentiation and dentine development through pAkt/pErk42/44/Dlx3/Sp7/GCN5/Dspp/Dmp1.
PubMed: 37790473
DOI: 10.21203/rs.3.rs-3299295/v1 -
The Chinese Journal of Dental Research Mar 2024The dentine sialophosphoprotein (DSPP) gene is the only identified causative gene for dentinogenesis imperfecta type 2 (DGI-II), dentinogenesis imperfecta type 3... (Review)
Review
The dentine sialophosphoprotein (DSPP) gene is the only identified causative gene for dentinogenesis imperfecta type 2 (DGI-II), dentinogenesis imperfecta type 3 (DGI-III) and dentine dysplasia type 2 (DD-II). These three disorders may have similar molecular mechanisms involved in bridging the DSPP mutations and the resulting abnormal dentine mineralisation. The DSPP encoding proteins DSP (dentine sialoprotein) and DPP (dentine phosphoprotein) are positive regulators of dentine formation and perform a function during dentinogenesis. The present review focused on the recent findings and viewpoints regarding the relationship between DSPP and dentinogenesis as well as mineralisation from multiple perspectives, involving studies relating to spatial structure and tissue localisation of DSPP, DSP and DPP, the biochemical characteristics and biological function of these molecules, and the causative role of the proteins in phenotypes of the knockout mouse model and in hereditary dentine defects.
Topics: Animals; Mice; Calcification, Physiologic; Calcinosis; Dentin; Dentinogenesis Imperfecta; Disease Models, Animal; Mice, Knockout; Humans; Sialoglycoproteins; Phosphoproteins
PubMed: 38546516
DOI: 10.3290/j.cjdr.b5136791 -
International Endodontic Journal Aug 2023Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel...
AIM
Biallelic loss-of-function FAM20A mutations cause amelogenesis imperfecta (AI) type IG, better known as enamel renal syndrome (ERS), characterized by severe enamel hypoplasia, delayed/failed tooth eruption, intrapulpal calcifications, gingival hyperplasia and nephrocalcinosis. FAM20A binds to FAM20C, the Golgi casein kinase (GCK) and potentiates its function to phosphorylate secreted proteins critical for biomineralization. While many FAM20A pathogenic mutations have been reported, the pathogeneses of orodental anomalies in ERS remain to be elucidated. This study aimed to identify disease-causing mutations for patients with ERS phenotypes and to discern the molecular mechanism underlying ERS intrapulpal calcifications.
METHODOLOGY
Phenotypic characterization and whole exome analyses were conducted for 8 families and 2 sporadic cases with hypoplastic AI. A minigene assay was performed to investigate the molecular consequences of a FAM20A splice-site variant. RNA sequencing followed by transcription profiling and gene ontology (GO) analyses were carried out for dental pulp tissues of ERS and the control.
RESULTS
Biallelic FAM20A mutations were demonstrated for each affected individual, including 7 novel pathogenic variants: c.590-5T>A, c.625T>A (p.Cys209Ser), c.771del (p.Gln258Argfs*28), c.832_835delinsTGTCCGACGGTGTCCGACGGTGTC CA (p.Val278Cysfs*29), c.1232G>A (p.Arg411Gln), c.1297A>G (p.Arg433Gly) and c.1351del (p.Gln451Serfs*4). The c.590-5T>A splice-site mutation caused Exon 3 skipping, which resulted in an in-frame deletion of a unique region of the FAM20A protein, p.(Asp197_Ile214delinsVal). Analyses of differentially expressed genes in ERS pulp tissues demonstrated that genes involved in biomineralization, particularly dentinogenesis, were significantly upregulated, such as DSPP, MMP9, MMP20 and WNT10A. Enrichment analyses indicated overrepresentation of gene sets associated with BMP and SMAD signalling pathways. In contrast, GO terms related to inflammation and axon development were underrepresented. Among BMP signalling genes, BMP agonists GDF7, GDF15, BMP3, BMP8A, BMP8B, BMP4 and BMP6 were upregulated, while BMP antagonists GREM1, BMPER and VWC2 showed decreased expression in ERS dental pulp tissues.
CONCLUSIONS
Upregulation of BMP signalling underlies intrapulpal calcifications in ERS. FAM20A plays an essential role in pulp tissue homeostasis and prevention of ectopic mineralization in soft tissues. This critical function probably depends upon MGP (matrix Gla protein), a potent mineralization inhibitor that must be properly phosphorylated by FAM20A-FAM20C kinase complex.
Topics: Humans; Nephrocalcinosis; Amelogenesis Imperfecta; Dental Pulp; Dental Enamel Proteins; Mutation; Calcinosis; Gene Expression Profiling; Carrier Proteins
PubMed: 37159186
DOI: 10.1111/iej.13928 -
Zhonghua Kou Qiang Yi Xue Za Zhi =... Aug 2023Dentin dysplasia type Ⅱ (DD-Ⅱ) is a subtype of hereditary dentin disorders. The dentin sialophosphoprotein (DSPP) gene has been revealed to be the causative gene,...
Dentin dysplasia type Ⅱ (DD-Ⅱ) is a subtype of hereditary dentin disorders. The dentin sialophosphoprotein (DSPP) gene has been revealed to be the causative gene, whose mutations could affect the normal tooth development process. The lesions involve both deciduous and permanent dentition, mainly manifested as tooth discoloration, attrition and even the subsequent malocclusion. If not treated in time, it will significantly affect the physical and psychological health of patients. The disease is difficult to be diagnosed in clinic accurately as its low incidence and hidden manifestations. The present article aims to discuss the clinical and radiographic characteristics, diagnosis, treatment of DD-Ⅱ, in order to improve the overall understanding on DD-Ⅱ for clinicians.
Topics: Humans; Dentin Dysplasia; Dentinogenesis Imperfecta; Sialoglycoproteins; Tooth; Mutation; Extracellular Matrix Proteins; Phosphoproteins; Dentin
PubMed: 37550036
DOI: 10.3760/cma.j.cn112144-20230410-00148 -
Calcified Tissue International May 2024Osteogenesis Imperfecta is a rare, hereditary bone condition with an incidence of 1/15,000-20,000. Symptoms include bone fragility, long bone deformity, scoliosis,... (Review)
Review
Osteogenesis Imperfecta is a rare, hereditary bone condition with an incidence of 1/15,000-20,000. Symptoms include bone fragility, long bone deformity, scoliosis, hypermobility, alongside secondary features such as short stature, basilar invagination, pulmonary and cardiac complications, hearing loss, dentinogenesis imperfecta and malocclusion. Osteogenesis Imperfecta can have a large impact on the child and their family; this impact starts immediately after diagnosis. Fractures, pain, immobility, hospital admissions and the need for equipment and adaptations all influence the health-related quality of life of the individual and their family. This narrative review article aims to examine the impact the diagnosis and management of osteogenesis imperfecta has on the health-related quality of life of a child. It will touch on the effect this may have on the quality of life of their wider family and friends and identify strategies to optimise health-related quality of life in this population. Optimising health-related quality of life in children with Osteogenesis Imperfecta is often a complicated, multifaceted journey that involves the child, their extended family, school, extracurricular staff and numerous health professionals.
PubMed: 38695871
DOI: 10.1007/s00223-024-01205-4 -
European Archives of Paediatric... Feb 2024Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation,...
BACKGROUND
Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation, respectively. Children and young people may be adversely affected by these conditions, with significant reduction in oral health related quality of life. Dental management of children with AI and DI is often complex, which is exacerbated by the absence of clear referral pathways and scarce evidence-based guidelines.
METHOD
The need for increased knowledge and peer support led to the development of a group of UK paediatric dentists with a special clinical interest in the management of children with AI and DI.
PURPOSE
The aims of this paper are to describe the establishment of an AI/DI Clinical Excellence Network (AI/DI CEN) in paediatric dentistry including outputs and future plans, and to share our collective learning to help support others anywhere in the world advance the care of people with AI or DI.
Topics: Child; Humans; Adolescent; Amelogenesis Imperfecta; Dentinogenesis Imperfecta; Quality of Life; Dentin; United Kingdom
PubMed: 38308725
DOI: 10.1007/s40368-023-00859-2 -
Calcified Tissue International Apr 2024Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the...
Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.
PubMed: 38641703
DOI: 10.1007/s00223-024-01213-4 -
Journal of Bone and Mineral Research :... Nov 2023As epigenetic regulators of gene expression, circulating micro-RiboNucleic Acids (miRNAs) have been described in several bone diseases as potential prognostic markers....
As epigenetic regulators of gene expression, circulating micro-RiboNucleic Acids (miRNAs) have been described in several bone diseases as potential prognostic markers. The aim of our study was to identify circulating miRNAs potentially associated with the severity of osteogenesis imperfecta (OI) in three steps. We have screened by RNA sequencing for the miRNAs that were differentially expressed in sera of a small group of OI patients versus controls and then conducted a validation phase by RT-qPCR analysis of sera of a larger patient population. In the first phase of miROI, we found 79 miRNAs that were significantly differentially expressed. We therefore selected 19 of them as the most relevant. In the second phase, we were able to validate the significant overexpression of 8 miRNAs in the larger OI group. Finally, we looked for a relationship between the level of variation of the validated miRNAs and the clinical characteristics of OI. We found a significant difference in the expression of two microRNAs in those patients with dentinogenesis imperfecta. After reviewing the literature, we found 6 of the 8 miRNAs already known to have a direct action on bone homeostasis. Furthermore, the use of a miRNA-gene interaction prediction model revealed a 100% probability of interaction between 2 of the 8 confirmed miRNAs and COL1A1 and/or COL1A2. This is the first study to establish the miRNA signature in OI, showing a significant modification of miRNA expression potentially involved in the regulation of genes involved in the physiopathology of OI. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Topics: Humans; Adult; Osteogenesis Imperfecta; MicroRNAs; Collagen Type I, alpha 1 Chain; Collagen Type I; Minerals; Mutation
PubMed: 37715362
DOI: 10.1002/jbmr.4912 -
Dental Abnormalities in Two Dental-Skeletal-Retinal Anomaly-Positive Cane Corso Dogs: A Case Series.Journal of Veterinary Dentistry Dec 2023Dental-skeletal-retinal-anomaly (DSRA) is a newly described collagenopathy in Cane Corso dogs. The causative mutation has been linked with splice defects within the...
Dental-skeletal-retinal-anomaly (DSRA) is a newly described collagenopathy in Cane Corso dogs. The causative mutation has been linked with splice defects within the melanoma inhibitory activity member 3 (MIA/3) gene that codes for the TANGO1 protein. This case series presents the first dental-related radiographic and histopathological abnormalities in two dogs with genetically confirmed DSRA. The clinical, radiological, and histological features are similar to those reported for MIA3/TANGO1 splice defects previously reported in humans and knockout mice. Common clinical features of these patients include generalized opalescent discoloration of the permanent dentition (intrinsic dyschromia), enamel defects, fractured teeth, vision loss, shortened physical stature, and orthopedic abnormalities that resulted in chronic, early-onset lameness. Intraoral radiography revealed delayed dentin deposition, evidence of endodontic disease, and dental hard tissue loss in both cases. Histopathologic findings for both cases were consistent with dentinogenesis imperfecta (DGI). DSRA exhibits autosomal recessive heritability and commercial diagnostic tests are now available. Clinicians should be aware of the etiopathogenesis, genetic inheritance and associated comorbidities in order to treat and counsel clients on the management of this condition. It is recommended that all breeding individuals be tested, and carriers be sterilized or omitted from the breeding population. This case study describes intraoral diagnoses, treatments, and follow-up of two DSRA-positive dogs.
PubMed: 38146186
DOI: 10.1177/08987564231215170