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Journal of Bone and Mineral Research :... Aug 2014Activating mutations in transient receptor potential vanilloid family member 4 (Trpv4) are known to cause a spectrum of skeletal dysplasias ranging from autosomal...
Activating mutations in transient receptor potential vanilloid family member 4 (Trpv4) are known to cause a spectrum of skeletal dysplasias ranging from autosomal dominant brachyolmia to lethal metatropic dysplasia. To develop an animal model of these disorders, we created transgenic mice expressing either wild-type or mutant TRPV4. Mice transgenic for wild-type Trpv4 showed no morphological changes at embryonic day 16.5 but did have a delay in bone mineralization. Overexpression of a mutant TRPV4 caused a lethal skeletal dysplasia that phenocopied many abnormalities associated with metatropic dysplasia in humans, including dumbbell-shaped long bones, a small ribcage, abnormalities in the autopod, and abnormal ossification in the vertebrae. The difference in phenotype between embryos transgenic for wild-type or mutant Trpv4 demonstrates that an increased amount of wild-type protein can be tolerated and that an activating mutation of this protein is required to produce a skeletal dysplasia phenotype.
Topics: Animals; Bone Development; Bone Diseases, Developmental; Chondrocytes; Gene Expression; Genetic Diseases, Inborn; Humans; Male; Mice; Mice, Transgenic; TRPV Cation Channels; Up-Regulation
PubMed: 24644033
DOI: 10.1002/jbmr.2220 -
Orthopaedic Surgery Feb 2020Metatropic dysplasia (MD), is a rare skeletal dysplasia occurring predominantly in infants characterized by a distinctive long torso and short limbs; it is as a result...
Metatropic dysplasia (MD), is a rare skeletal dysplasia occurring predominantly in infants characterized by a distinctive long torso and short limbs; it is as a result of mutations in the TRPV4 gene. However, a clear distinction between various forms of skeletal dysplasias caused by the transient receptor potential vanilloid 4 (TRPV4) gene is difficult but could be achieved by a combination of gene sequencing, medical and radiological criteria. We hereby report a case of a 14-month old girl who presented with an abnormal stature. The diagnosis of nonlethal MD was confirmed by X-ray with dumbbell-shaped long bones, platyspondyly, and delayed carpal ossification, as well as broadened pelvis with marginally widened ilia, epiphyseal plates, and slightly flattened acetabula. Furthermore, gene sequencing confirmed gene mutation on exon 15 of the TRPV4 gene with a heterozygous missense mutation (c.2396C > T), but no mutation was present in her parents. Our findings recorded metatropic dysplasia with the c.2396C > T mutation in the TRPV4 gene in China. This mutation caused changes in amino acid of TRPV4, which can induce growth retardation in children.
Topics: Asian People; China; Dwarfism; Female; Humans; Infant; Osteochondrodysplasias; Radiography
PubMed: 31808622
DOI: 10.1111/os.12546 -
Biochemistry and Biophysics Reports Sep 2019Metatropic dysplasia is a congenital skeletal dysplasia characterized by severe platyspondyly, dumbbell-like deformity of long tubular bones, and progressive...
Metatropic dysplasia is a congenital skeletal dysplasia characterized by severe platyspondyly, dumbbell-like deformity of long tubular bones, and progressive kyphoscoliosis with growth. It is caused by mutations in the gene , encoding the transient receptor potential vanilloid 4, which acts as a calcium channel. Many heterozygous single base mutations of this gene have been associated with the disorder, showing autosomal dominant inheritance. Although abnormal endochondral ossification has been observed by histological examination of bone in a patient with lethal metatropic dysplasia, the etiology of the disorder remains largely unresolved. As dental pulp stem cells (DPSCs) are mesenchymal stem cells that differentiate into bone lineage cells, DPSCs derived from patients with congenital skeletal dysplasia might be useful as a disease-specific cellular model for etiological investigation. The purpose of this study was to clarify the pathological association between mutation and chondrocyte differentiation by analyzing DPSCs from a patient with non-lethal metatropic dysplasia. We identified a novel heterozygous single base mutation, c.1855C>T in . This was predicted to be a missense mutation, p.L619F, in putative transmembrane segment 5. The mutation was repaired by CRISPR/Cas9 system to obtain isogenic control DPSCs for further analysis. The expression of stem cell markers and fibroblast-like morphology were comparable between patient-derived mutant and control DPSCs, although expression of TRPV4 was lower in mutant DPSCs than control DPSCs. Despite the lower TRPV4 expression in mutant DPSCs, the intracellular Ca level was comparable at the basal level between mutant and control DPSCs, while its level was markedly higher following stimulation with 4α-phorbol 12,13-didecanoate (4αPDD), a specific agonist for TRPV4, in mutant DPSCs than in control DPSCs. In the presence of 4αPDD, we observed accelerated early chondrocyte differentiation and upregulated mRNA expression of SRY-box 9 () in mutant DPSCs. Our findings suggested that the novel missense mutation c.1855C>T of was a gain-of-function mutation leading to enhanced intracellular Ca level, which was associated with accelerated chondrocyte differentiation and upregulation. Our results also suggest that patient-derived DPSCs can be a useful disease-specific cellular model for elucidating the pathological mechanism of metatropic dysplasia.
PubMed: 31463371
DOI: 10.1016/j.bbrep.2019.100648 -
Journal of Orthopaedic Surgery and... Oct 2016A lot of advantages can result in a high wettability as well as a nanostructure at a titanium surface on bone implants. Thus, the aim of this study was to evaluate the...
BACKGROUND
A lot of advantages can result in a high wettability as well as a nanostructure at a titanium surface on bone implants. Thus, the aim of this study was to evaluate the osseointegrative potential of a titan plasma-sprayed (TPS) surface refinement by acid-etching with chromosulfuric acid. This results in a hyperhydrophilic surface with a nanostructure and an extreme high wetting rate.
METHODS
In total, 72 dumbbell shape titan implants were inserted in the spongy bone of the femora of 18 Göttingen minipigs in a conservative gap model. Thirty-six titan implants were coated with a standard TPS surface and 36 with the hyperhydrophilic chromosulfuric acid (CSA) surface. After a healing period of 4, 8, and 12 weeks, the animals were killed. The chronological healing process was histomorphometrically analyzed.
RESULTS
The de novo bone formation, represented by the bone area (BA), is increased by approximately 1.5 times after 12 weeks with little additional benefit by use of the CSA surface. The bone-to-implant contact (BIC), which represents osseoconductive forces, shows results with a highly increased osteoid production in the CSA implants beginning at 8 and 12 weeks compared to TPS. This culminates in a 17-fold increase in BIC after a healing period of 12 weeks. After 4 weeks, significantly more osteoid was seen in the gap as de novo formation in the CSA group (p = 0.0062). Osteoid was also found more frequently after 12 weeks at the CSA-treated surface (p = 0.0355). The site of implantation, intertrochanteric or intercondylar, may influence on the de novo bone formation in the gap.
CONCLUSIONS
There is a benefit by the CSA surface treatment of the TPS layer for osseointegration over an observation time up to 12 weeks. Significant differences were able to be shown in two direct comparisons between the CSA and the TPS surface for osteoid formation in the gap model. Further trials may reveal the benefit of the CSA treatment of the TPS layer involving mechanical tests if possible.
Topics: Animals; Coated Materials, Biocompatible; Female; Femur; Implants, Experimental; Microscopy, Electron, Scanning; Models, Animal; Nanostructures; Osseointegration; Osteogenesis; Stress, Mechanical; Surface Properties; Swine; Swine, Miniature; Titanium
PubMed: 27751181
DOI: 10.1186/s13018-016-0434-6 -
American Journal of Medical Genetics.... Aug 2010We report on two sibs with a lethal form of bone dysplasia with distinctive skeletal findings including rhizomelic and mesomelic limb shortening, hooked clavicles,...
We report on two sibs with a lethal form of bone dysplasia with distinctive skeletal findings including rhizomelic and mesomelic limb shortening, hooked clavicles, dumbbell femurs, and absence of talus and calcaneus ossification. Other clinical features include Dandy-Walker malformation, congenital heart defects, joint contractures, genital hypoplasia, and distinctive facial features. These sibs appear to have a previously undescribed skeletal dysplasia, which is most likely inherited in an autosomal recessive fashion.
Topics: Abnormalities, Multiple; Adult; Dandy-Walker Syndrome; Face; Fatal Outcome; Female; Genitalia; Heart Defects, Congenital; Humans; Infant, Newborn; Male; Musculoskeletal Abnormalities; Thumb
PubMed: 20602491
DOI: 10.1002/ajmg.a.33488 -
Journal of Bone and Mineral Research :... Feb 2003Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were measured in a mild case of dyssegmental dysplasia. X-ray pictures of a female...
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were measured in a mild case of dyssegmental dysplasia. X-ray pictures of a female baby born vaginally at 39 weeks of gestation showed short, bent, dumbbell-shaped long bones of the limbs and profound dyssegmental ossification in the spine, findings characteristic of dyssegmental dysplasia. When the levels of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured, the levels of MMP-2 and TIMP-1 were significantly reduced. This case might provide a clue to disclose the etiology of dyssegmental dysplasia.
Topics: Bone Diseases, Developmental; Bone and Bones; Dwarfism; Female; Fetal Blood; Humans; Infant, Newborn; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Phenotype; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2
PubMed: 12568417
DOI: 10.1359/jbmr.2003.18.2.381