Evaluation of alveolar bone hypomineralization in pediatric hypophosphatasia using orthopantomography.
Ontology highlight
ABSTRACT:
SUBMITTER: Okawa R
PROVIDER: S-EPMC8786966 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hypophosphatasia (HPP) is a rare genetic disease characterized by a decrease in the activity of tissue non-specific alkaline phosphatase (TNSALP). TNSALP is encoded by the ALPL gene, which is abundantly expressed in the skeleton, liver, kidney, and developing teeth. HPP exhibits high clinical variability largely due to the high allelic heterogeneity of the ALPL gene. HPP is characterized by multisystemic complications, although the most common clinical manifestations are those that occur in the skeleton, muscles, and teeth. These complications are mainly due to the accumulation of inorganic pyrophosphate (PPi) and pyridoxal-5'-phosphate (PLP). It has been observed that the prevalence of mild forms of the disease is more than 40 times the prevalence of severe forms. Patients with HPP present at least one mutation in the ALPL gene. However, it is known that there are other causes that lead to decreased alkaline phosphatase (ALP) levels without mutations in the ALPL gene. Although the phenotype can be correlated with the genotype in HPP, the prediction of the phenotype from the genotype cannot be made with complete certainty. The availability of a specific enzyme replacement therapy for HPP undoubtedly represents an advance in therapeutic strategy, especially in severe forms of the disease in pediatric patients.
| S-EPMC8122659 | biostudies-literature
Project description:Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. However, the biochemical pathways that generate intravesicular PHOSPHO1 substrates are currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase 6 (ENPP6) is an upstream source of the PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6 -/- ). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6 -/- tibias (p < 0.05) that normalized by 12 weeks of age. Whole-bone cortical analysis also revealed significantly hypomineralized proximal bone in 4- but not 12-week-old Enpp6 -/- mice (p < 0.05) compared with WT animals. Back-scattered SEM revealed a failure in 4-week-old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p > 0.01) and osteoid surface (p < 0.05), which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6 -/- mice, revealing transient hypomineralization in young animals compared with WT controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
| S-EPMC7872340 | biostudies-literature
Project description:AimThe objective of this research was to perform a pilot study to develop an automatic analysis of periapical radiographs from patients with and without periodontitis for the percentage alveolar bone loss (ABL) on the approximal surfaces of teeth using a supervised machine learning model, that is, convolutional neural networks (CNN).Material and methodsA total of 1546 approximal sites from 54 participants on mandibular periapical radiographs were manually annotated (MA) for a training set (n = 1308 sites), a validation set (n = 98 sites), and a test set (n = 140 sites). The training and validation sets were used for the development of a CNN algorithm. The algorithm recognised the cemento-enamel junction, the most apical extent of the alveolar crest, the apex, and the surrounding alveolar bone.ResultsFor the total of 140 images in the test set, the CNN scored a mean of 23.1 ± 11.8 %ABL, whilst the corresponding value for MA was 27.8 ± 13.8 %ABL. The intraclass correlation (ICC) was 0.601 (P < .001), indicating moderate reliability. Further subanalyses for various tooth types and various bone loss patterns showed that ICCs remained significant, although the algorithm performed with excellent reliability for %ABL on nonmolar teeth (incisors, canines, premolars; ICC = 0.763).ConclusionsA CNN trained algorithm on radiographic images showed a diagnostic performance with moderate to good reliability to detect and quantify %ABL in periapical radiographs.
| S-EPMC9485533 | biostudies-literature
Project description:Bone tissue regeneration is orchestrated by the surrounding supporting tissues and involves the build-up of osteogenic cells, which orchestrate remodeling/healing through the expression of numerous mediators and signaling molecules. Periodontal regeneration models have proven useful for studying the interaction and communication between alveolar bone and supporting soft tissue. We applied a quantitative proteomic approach to analyze and compare proteins with altered expression in gingival soft tissue and alveolar bone following tooth extraction. For target identification and validation, hard and soft tissue were extracted from mini-pigs at the indicated times after tooth extraction. From triplicate experiments, 56 proteins in soft tissue and 27 proteins in alveolar bone were found to be differentially expressed before and after tooth extraction. The expression of 21 of those proteins was altered in both soft tissue and bone. Comparison of the activated networks in soft tissue and alveolar bone highlighted their distinct responsibilities in bone and tissue healing. Moreover, we found that there is crosstalk between identified proteins in soft tissue and alveolar bone with respect to cellular assembly, organization, and communication. Among these proteins, we examined in detail the expression patterns and associated networks of ATP5B and fibronectin 1. ATP5B is involved in nucleic acid metabolism, small molecule biochemistry, and neurological disease, and fibronectin 1 is involved in cellular assembly, organization, and maintenance. Collectively, our findings indicate that bone regeneration is accompanied by a profound interaction among networks regulating cellular resources, and they provide novel insight into the molecular mechanisms involved in the healing of periodontal tissue after tooth extraction.
| S-EPMC3790282 | biostudies-literature
Project description:Hypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene-encoding tissue-nonspecific isozyme of alkaline phosphatase. In this 13-week, phase 2a, multicenter, randomized, open-label, dose-response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric-onset hypophosphatasia. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration-time curve from time 0 to infinity) to asfotase alfa increased between single- and multiple-dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration-time profiles within each dose cohort. Median terminal elimination half-life was ≈5 days following multiple-dose administration, with steady state achieved by approximately day 29. Dose-normalized exposure data indicated that asfotase alfa activity was approximately dose-proportional within the studied dose range. Additionally, dose-normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m2 , indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric-onset hypophosphatasia.
| S-EPMC8518624 | biostudies-literature
Project description:PurposeThe aims of this retrospective cross-sectional study were to measure and compare labial and palatal alveolar bone heights of maxillary central incisors in unilateral cleft lip and palate patients, following STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.Patients and methodsThe study group consisted of 21 patients with a mean age of 16 years. High-resolution cone-beam computed tomography was performed at least one year after secondary alveolar bone grafting. The experimental side was the cleft side and the contralateral side without congenital cleft was the control. Measurements were performed on incisors' midsagittal cross-sections. The Wilcoxon signed-rank test was used for intergroup comparisons.ResultsThe labial and palatal distances between alveolar bone crests and cementoenamel junctions were significantly greater on the cleft side than on the noncleft side. Mean differences were 0.75 and 1.41 mm, respectively. The prevalence of dehiscences at the cleft side maxillary central incisors was 52% on the labial surface and 43% on the palatal surface. In the controls, it was 19% and 14%, respectively.ConclusionThe cleft-adjacent maxillary central incisors had more apically displaced alveolar bone crests on the labial and palatal sides of the roots than the controls. Higher prevalence of dehiscences was found on the cleft side. Bone margin differences predispose to gingival height differences of the central incisors. These differences could increase the demands of patients to obtain more esthetic treatment results with orthodontic extrusion and periodontal intervention on the cleft side.
| S-EPMC8076140 | biostudies-literature
Project description:The aim of this paper is to investigate the effect that bone marrow mesenchymal stem cells (BMMSCs) - endothelial progenitor cells (EPCs), BMMSCs and EPCs sheets have on repairing maxillary alveolar defects in ovariectomized (OVX) rats. In this study, after identification using multi-lineage differentiation and flow cytometry, BMMSCs and EPCs were isolated from female rats. The BMMSCs-EPCs, BMMSCs and EPCs sheets were detected by hematoxylin-eosin (H&E) staining, alkaline phosphatase (ALP) staining and qRT-PCR. Defects were created in maxillary alveoli and repaired with BMMSCs-EPCs, BMMSCs and EPCs sheets in OVX rats. The repair effects were determined by histological staining and micro-CT analysis at 2, 4 and 8 weeks after implantation. We aim to clarify whether BMMSCs-EPCs sheets are more effective in repairing alveolar bone defects than are BMMSCs and EPCs sheets in OVX rats. The results show that the osteogenic potential and the effect of bone repair are greater in the BMMSCs-EPCs sheet group and that this group has a higher ability to repair alveolar bone defects in OVX rats. These results suggest that BMMSCs-EPCs sheets have potential in clinical applications for treating humans with osteoporosis.
| S-EPMC5707386 | biostudies-literature
Project description:In adult hypophosphatasia (HPP) patients, elevated lumbar spine dual X-ray absorptiometry (DXA) values are associated with markers of disease severity and disease-specific fracture risk while femoral bone mineral density (BMD), being largely unaffected by the disease severity, may still be useful to monitor other causes of increased fracture risk due to low BMD.IntroductionHypophosphatasia (HPP) is a rare inherited metabolic disorder due to deficient activity of the tissue-nonspecific alkaline phosphatase (TNAP). Clinical manifestation in adult HPP patients is manifold including an increased risk for fractures, but data regarding clinical significance of DXA measurement and associations with fracture risk and disease severity is scarce.MethodsRetrospective single-center analysis of DXA scans in patients with confirmed HPP (documented mutation, clinical symptoms, low alkaline phosphatase activity). Further data evaluation included disease-related fractures, laboratory results (alkaline phosphatase, pyridoxalphosphate, phosphoethanolamine), and medical history.ResultsAnalysis included 110 patients (84 female, mean age of 46.2 years) of whom 37.3% (n = 41) were harboring two mutations. Average T-Score level at the lumbar spine was - 0.1 (SD 1.9), and mean total hip T-Score was - 1.07 (SD 0.15). Both lower ALP activity and higher substrate levels (pyridoxalphosphate and phosphoethanolamine) were significantly correlated with increased lumbar spine T-Score levels (p < 0.001) while BMD at the hip was not affected by indicators of disease severity. Increased lumbar spine BMD was significantly associated with an increased risk for HPP-related fractures, prevalent in 22 (20%) patients (p < 0.001) with 21 of them having biallelic mutations.ConclusionBMD in adult HPP patients is not systematically reduced. Conversely, increased lumbar spine BMD appears to be associated with severely compromised mineralization and increased risk for HPP-related fractures while BMD at the hip appears unaffected by indicators of disease severity, suggesting suitability of this anatomic location for assessing and discerning disorders with increased fracture risk owing to reduced BMD like osteoporosis.Trial registration numberGerman register for clinical studies (DRKS00014022) DATE OF REGISTRATION: 02/10/2018 - retrospectively registered.
| S-EPMC7838076 | biostudies-literature
Project description:BackgroundThe use of palatal miniscrew offers the possibility to improve the effectiveness of orthodontic expansion devices. Palatal expanders supported by miniscrew can be applied with different clinical protocols. Some authors proposed the use of four palatal miniscrews during miniscrew-supported palatal expansion to maximize skeletal effects in young adults' treatment. However, bone availability decreases in the posterior paramedian palatal regions, making the positioning of the two-posterior paramedian palatal miniscrews challenging, when it is performed avoiding nasal cavities invasion. Some authors proposed miniscrews insertion in a specific region located laterally to the palatal process of the maxillary bone, and apically relatively to the dento-alveolar process. The aim of this study was to evaluate the bone thickness, cortical bone thickness, and mucosae depth of this anatomical site that, in this study, was defined as palatal posterior supra-alveolar insertion site.ResultsThe evaluation of bone availability of palatal posterior supra-alveolar insertion site at different antero-posterior levels showed that the maximum amount of total bone thickness was found between the second premolar and the first molar. At this level total bone, thickness is significantly (p < .05) greater compared to the other sagittal sites and it offers on average around 2 mm of extra bone depth for miniscrew placement. Cortical bone thickness is adequate for primary miniscrew stability. Overall, cortical bone thickness considered at different insertion sites showed significant statistically (p < .05) differences. The findings of this study showed that palatal mucosa is particularly thick with average values ranging from 4 to 7 mm, and its extension ultimately affects miniscrew length selection. Palatal mucosa thickness showed no clinically significant differences comparing different sagittal and vertical insertion sites. Data also showed that palatal mucosal thickness slightly significantly increases (p < .05) with the inclination of the insertion axis relative to the occlusal plane. Finally, study findings showed that vertical growth pattern can significantly affect considered outcomes (p < .05).ConclusionsPalatal posterior supra-alveolar insertion site is an appropriate site for posterior insertion of palatal miniscrews. Considering high anatomical variation preliminary CBCT evaluation is important to achieve optimal miniscrew placement.
| S-EPMC9167746 | biostudies-literature
Project description:(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014−2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein.
| S-EPMC9654387 | biostudies-literature