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European Journal of Medical Genetics Nov 2023Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only...
Pathogenic variants in SPARC cause a rare autosomal recessive form of osteogenesis imperfecta (OI), classified as OI type XVII, which was first reported in 2015. Only six patient cases with this specific form of OI have been reported to date. The SPARC protein plays a crucial role in the calcification of collagen in bone, synthesis of the extracellular matrix, and the regulation of cell shape. In this case report, we describe the phenotype of two patients with SPARC-related OI, including a patient with two novel pathogenic variants in the SPARC gene. Targeted Next Generation Sequencing revealed new compound heterozygous variants (c.484G > A p.(Glu162Lys)) and c.496C > T p.(Arg166Cys)) in one patient and a homozygous nonsense pathogenic variant (c.145C > T p.(Gln49*)) in the other. In line with previously reported cases, the two OI patients presented delayed motor development, muscular weakness, scoliosis, and multiple fractures. Interestingly, our study reports for the first time the occurrence of dentinogenesis imperfecta. The study also reports the effectiveness of bisphosphonate treatment for OI type XVII. This article enhances the genetic, clinical, therapeutic, and radiological understanding of SPARC-related OI.
Topics: Humans; Osteogenesis Imperfecta; Mutation; Phenotype; Homozygote; Bone and Bones; Collagen Type I; Osteonectin
PubMed: 37758164
DOI: 10.1016/j.ejmg.2023.104857 -
European Journal of Medical Genetics Nov 2023Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and...
Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management.
Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia. We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision. Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia. In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.
Topics: Child; Humans; Osteogenesis Imperfecta; Hypophosphatasia; Osteomalacia; Fractures, Multiple; Mutation; Alkaline Phosphatase; Calcinosis; Rickets
PubMed: 37758163
DOI: 10.1016/j.ejmg.2023.104856 -
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 -
European Journal of Paediatric Dentistry Jun 2024To investigate the effect of 38% SDF and its serial dilutions on the Stem cells from Human Exfoliated Deciduous teeth (SHED) and its ability to release growth factors...
AIM
To investigate the effect of 38% SDF and its serial dilutions on the Stem cells from Human Exfoliated Deciduous teeth (SHED) and its ability to release growth factors from deciduous dentine.
METHODS
The viability of SHED post-exposure to 38%, 3.8%, 0.38%, 0.038%, and 0.0038% SDF were assessed at 2, 5, and 7 days using the CyQuant assay, and results were validated using the MTT assay. The osteogenic differentiation of the cells was also investigated post-exposure to 0.0038% SDF. The release of the growth factors; TGF-β1, FGF-b, BMP-2, and VEGF from deciduous dentin discs exposed to 38% SDF, 0.0038% SDF, Ca(OH)2, MTA, and 17% EDTA were examined using ELISA. Statistical analysis was performed using means and standard deviations (p < 0.05). Two-way ANOVA compared the means of more than two groups with Tukey's multiple comparison test. The unpaired t-test was also used to compare the differences between the two data sets.
CONCLUSION
38% SDF released dentinogenic growth factors from dentin discs, potentially explaining its role in reactionary dentinogenesis. Moreover, 0.0038% SDF resulted in a non-cytotoxic concentration that enhanced cellular proliferation and released bioactive molecules from dentin comparable to the 38% concentration. After further investigations, the 0.0038% dilution of SDF could present itself as a clinical concentration.
Topics: Humans; Tooth, Deciduous; Quaternary Ammonium Compounds; Dentin; Stem Cells; Silver Compounds; Cell Survival; Bone Morphogenetic Protein 2; Fluorides, Topical; Cell Differentiation; Osteogenesis; Vascular Endothelial Growth Factor A; Transforming Growth Factor beta1; Silicates; In Vitro Techniques; Calcium Compounds; Cells, Cultured; Calcium Hydroxide; Drug Combinations; Oxides; Aluminum Compounds
PubMed: 37691596
DOI: 10.23804/ejpd.2023.1928 -
Journal of Applied Oral Science :... 2023Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. OI is also known as... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Osteogenesis imperfecta (OI) is a rare genetic disorder primarily caused by mutations in the genes involved in the production of type 1 collagen. OI is also known as brittle bone disease.
OBJECTIVE
This study aims to describe the prevalence of dental anomalies (except dentinogenesis imperfecta) in individuals with OI, and compare the prevalence of dental anomalies between individuals with and without OI and between individuals with different types of OI.
SEARCH METHODS
Searches in PubMed, Web of Science, Scopus, Ovid, and gray literature were performed in October 2022.
SELECTION CRITERIA
Observational studies (with or without a comparison group) that evaluated the prevalence of dental anomalies in individuals with OI. Data collection and analysis: Data items were extracted by two authors. Quality assessment employing the Joanna Briggs Institute checklists and meta-analyses was conducted. Results were provided in prevalence values and odds ratio (OR) / 95% confidence interval (CI). Strength of evidence was determined.
RESULTS
Eighteen studies were included. Most prevalent dental anomalies in individuals with OI included pulp obliteration (46.4%), dental impaction (33.5%), dental impaction of second molars (27%), and tooth agenesis (23.9%). Individuals with OI type III/IV had 20.16-fold greater chance of exhibiting tooth discoloration in comparison with individuals with OI type I (CI: 1.10-370.98). In comparison with the group without OI, the individuals with OI had 6.90-fold greater chance of exhibiting dental impaction (CI: 1.54-31.00). High methodological quality was found in 47% of the studies. Strength of evidence was low or very low.
CONCLUSIONS
Pulp obliteration, dental impaction, and tooth agenesis were the most prevalent dental anomalies in the OI group. Individuals with OI were more likely to have dental impaction than individuals without OI. Individuals with OI type III/IV (severe-moderate) are more likely to have tooth discoloration than individuals with OI type I (mild).
Topics: Humans; Osteogenesis Imperfecta; Prevalence; Tooth Discoloration
PubMed: 37672427
DOI: 10.1590/1678-7757-2023-0040 -
Cells Jul 2023The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there...
The odontoblastic differentiation of dental pulp stem cells (DPSCs) associated with caries injury happens in an inflammatory context. We recently demonstrated that there is a link between inflammation and dental tissue regeneration, identified via enhanced DPSC-mediated dentinogenesis in vitro. Brain-derived neurotrophic factor (BDNF) is a nerve growth factor-related gene family molecule which functions through tropomyosin receptor kinase B (TrkB). While the roles of BDNF in neural tissue repair and other regeneration processes are well identified, its role in dentinogenesis has not been explored. Furthermore, the role of BDNF receptor-TrkB in inflammation-induced dentinogenesis remains unknown. The role of BDNF/TrkB was examined during a 17-day odontogenic differentiation of DPSCs. Human DPSCs were subjected to odontogenic differentiation in dentinogenic media treated with inflammation inducers (LTA or TNFα), BDNF, and a TrkB agonist (LM22A-4) and/or antagonist (CTX-B). Our data show that BDNF and TrkB receptors affect the early and late stages of the odontogenic differentiation of DPSCs. Immunofluorescent data confirmed the expression of BDNF and TrkB in DPSCs. Our ELISA and qPCR data demonstrate that TrkB agonist treatment increased the expression of dentin matrix protein-1 (DMP-1) during early DPSC odontoblastic differentiation. Coherently, the expression levels of runt-related transcription factor 2 (RUNX-2) and osteocalcin (OCN) were increased. TNFα, which is responsible for a diverse range of inflammation signaling, increased the levels of expression of dentin sialophosphoprotein (DSPP) and DMP1. Furthermore, BDNF significantly potentiated its effect. The application of CTX-B reversed this effect, suggesting TrkB`s critical role in TNFα-mediated dentinogenesis. Our studies provide novel findings on the role of BDNF-TrkB in the inflammation-induced odontoblastic differentiation of DPSCs. This finding will address a novel regulatory pathway and a therapeutic approach in dentin tissue engineering using DPSCs.
Topics: Humans; Tumor Necrosis Factor-alpha; Receptor, trkB; Tropomyosin; Brain-Derived Neurotrophic Factor; Dental Pulp; Cell Differentiation; Inflammation; Stem Cells
PubMed: 37508514
DOI: 10.3390/cells12141851 -
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 -
Dental Materials Journal Aug 2023Post-operative sensitivity (POS) is the most common clinical dental complaint after tooth preparation and resin-based composite restoration. In our previous study,...
Post-operative sensitivity (POS) is the most common clinical dental complaint after tooth preparation and resin-based composite restoration. In our previous study, copine 7 (CPNE7) and CPNE7-derived peptide (CPNE7-DP) induced in vitro odontoblast differentiation and in vivo dentin formation. Here, we incorporated CPNE7-DP into All-Bond Universal (ABU) adhesive, developing ABU/CPNE7-DP. This study aimed to investigate the possibility of reducing POS using ABU/CPNE7-DP. We first determined the stability of CPNE7-DP under low pH. Furthermore, we evaluated its dentinal tubule penetration, in vitro odontogenic differentiation potential, in vivo tertiary dentin formation and its effects on bonding performance. CPNE7-DP was stable at pH 1.2, even lower than ABU's pH of 3.2. ABU/CPNE7-DP can penetrate dentinal tubules, stimulate odontoblast differentiation in vitro and generate tertiary dentin with tubular structure in vivo without interfering with bonding performance. Therefore, ABU/CPNE7-DP may serve as a novel bioactive adhesive for reducing POS.
Topics: Dental Cements; Dental Materials; Peptides; Dentin; Dental Bonding; Dentin-Bonding Agents; Resin Cements; Materials Testing; Tensile Strength; Composite Resins
PubMed: 37271544
DOI: 10.4012/dmj.2022-181 -
Frontiers in Endocrinology 2023Osteogenesis imperfecta (OI) is a hereditary skeletal dysplasia with an incidence of approximately 1:15,000 to 20,000. OI is usually caused by the mutation of COL1A1 and...
UNLABELLED
Osteogenesis imperfecta (OI) is a hereditary skeletal dysplasia with an incidence of approximately 1:15,000 to 20,000. OI is usually caused by the mutation of COL1A1 and COL1A2, which would encode the α-chain of type I collagen. OI is clinically characterized by decreased bone mass, increased risk of bone fragility, blue sclerae, and dentinogenesis.
CASE PRESENTATION
A 29-year-old male patient was diagnosed with right tibial plateau fracture caused by slight violence. Physical examination revealed the following: height, 140 cm; weight, 70 kg; body mass index (BMI), 35.71 kg/m; blue sclera and barrel chest were observed. X-ray examination showed left convex deformity of the thoracic vertebrae with reduced thoracic volume. Laboratory examinations revealed a decrease in both vitamin D and blood calcium levels. Bone mineral density (BMD) was lower than the normal range. After the preoperative preparation was completed, the open reduction and internal fixation of the right tibial plateau fracture were performed. Meanwhile, whole blood samples of this OI patient and the normal control were collected for RNA transcriptome sequencing. The RNA sequence analysis revealed that there were 513 differentially expressed genes (DEGs) between this OI patient and the normal control. KEGG-enriched signaling pathways were significantly enriched in extracellular matrix (ECM)-receptor interactions.
CONCLUSION
In this case, DEGs between this OI patient and the normal control were identified by RNA transcriptome sequencing. Moreover, the possible pathogenesis of OI was also explored, which may provide new evidence for the treatment of OI.
Topics: Male; Humans; Adult; Osteogenesis Imperfecta; Tibial Plateau Fractures; Mutation; Fractures, Bone
PubMed: 37229455
DOI: 10.3389/fendo.2023.1164386