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Scientific Reports Oct 2017Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely...
Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2α1(Col2α1)-Cre- and collagen 10α1(Col10α1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using "Cre-loxP"-mediated gene excision. Mice lacking SHP2 in Col2α1-Cre-expressing cells die at mid-gestation. Postnatal SHP2 ablation in the same cell population caused dwarfism, chondrodysplasia and exostoses. In contrast, mice in which SHP2 was ablated in the Col10α1-Cre-expressing cells appeared normal but were osteopenic. Further mechanistic studies revealed that SHP2 exerted its influence partly by regulating the abundance of SOX9 in chondrocytes. Elevated and sustained SOX9 in SHP2-deficient hypertrophic chondrocytes impaired their differentiation to osteoblasts and impaired endochondral ossification. Our study uncovered an important role of SHP2 in bone development and cartilage homeostasis by influencing the osteogenic differentiation of hypertrophic chondrocytes and provided insight into the pathogenesis and potential treatment of skeletal diseases, such as osteopenia and osteoporosis.
Topics: Animals; Bone Development; Bone Neoplasms; Cartilage; Cell Differentiation; Cell Proliferation; Cell Transdifferentiation; Chondrocytes; Chondrogenesis; Chondromatosis; Exostoses, Multiple Hereditary; Growth Plate; Humans; Hypertrophy; Mice; Osteoblasts; Osteogenesis; Protein Tyrosine Phosphatase, Non-Receptor Type 11; SOX9 Transcription Factor
PubMed: 28983104
DOI: 10.1038/s41598-017-12767-9 -
Journal of Orthopaedic Surgery (Hong... Aug 2016
Topics: Humans; Osteochondroma; Osteochondromatosis; Patella; Patellar Ligament
PubMed: 27574283
DOI: 10.1177/1602400239 -
BioMed Research International 2021To discuss the mutational features and their relationships with disease in a family with hereditary multiple osteochondroma (HMO) from Guangxi Province (GXBB-1 family),...
OBJECTIVES
To discuss the mutational features and their relationships with disease in a family with hereditary multiple osteochondroma (HMO) from Guangxi Province (GXBB-1 family), China.
METHODS
Genomic DNA and total mRNA were extracted from peripheral blood cells of GXBB-1 family members. Whole elements of the gene and its transcript, including exons, introns, exon-intron boundaries, and coding sequence (CDS) clones, were amplified and sequenced. Allele-specific PCR was used to confirm the position and type of mutation.
RESULTS
All patients from the GXBB-1 family harbored the cosegregating heterozygous c.1056+1G>A mutation located in at an exon-intron boundary. Another three single-nucleotide polymorphisms (SNPs) were also detected in the patients, including IVS2+1G>A in intron 2, c.1844 T>C [p.Pro (CCT) 614Pro (CCC)] in exon 3, and c.2534G>A [p.Glu (GAG) 844Glu (GAA)] in exon 9. The latter two SNPs were synonymous variations.
CONCLUSIONS
The heterozygous c.1056+1G>A mutation cosegregated with the phenotype, indicating that it is a pathogenic mutation in the GXBB-1 family. This mutation is reported for the first time in Chinese HMO patients. IVS2+1G>A and c.2534G>A have no relationship with the occurrence of disease. However, c.1844 T>C and c.1056+1G>A are linked, and their interaction needs to be further studied. c.1844T>C is a new SNP that has not been reported internationally.
Topics: Asian People; China; DNA Mutational Analysis; Exostoses, Multiple Hereditary; Female; Humans; Male; Mutation; N-Acetylglucosaminyltransferases; Pedigree; Polymorphism, Single Nucleotide; Sequence Analysis, DNA
PubMed: 34409107
DOI: 10.1155/2021/8888948 -
Orthopaedic Surgery Jun 2020To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical...
OBJECTIVE
To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical outcome and genotype in patients with hereditary multiple exostoses (HME).
METHODS
The study recruited seven families diagnosed with multiple osteochondromas (MO). Family histories and clinical information were collected in detail through comprehensive physical and image examination. Patients with deformities and functional limitations were classified as "severe" and the remaining without functional limitations were classified as "mild," in accordance with previous study. Whole-exome sequencing (WES) was performed on a total of 13 affected individuals, 1 available unaffected relative, and 10 healthy unrelated individuals. Sanger sequencing was used to validate the screened mutations. Finally, the structural change in protein caused by pathogenic mutations was analyzed using information from the relevant database online and we attempted to correlate clinical phenotype with genotype in patients with HME.
RESULTS
Other than EXT1 and EXT2, no novel potential gene mutations were found through WES. We identified nine heterozygous mutations in EXT1 or EXT2. Of these mutations, four have not been reported previously. These are c.996delT in exon 2 of EXT1 (family 1), c.544C > T in exon 3 of EXT2 (family 2), c.1171C > T in exon 7 of EXT2 (family 5), and c.823 824delAA in exon 5 of EXT1 (family 7). The other five mutations have already been reported in previous works. It was surprising that we found two mutation sites, in exon 2 and exon 5, respectively, of EXT1 in 1 patient diagnosed with MO, when his father had two mutation sites, in exon 6 and exon 5, respectively, of EXT1 and EXT2 (family 4). In addition, 1 patient showed degeneration, while his father only exhibited slight symptoms (family 7). In our study, among 51 affected patients in seven families, the sex ratio (male vs female) was 58.9% (n = 30) vs 41.2% (n = 21). Male patients seemed to show more severe symptoms compared to females, but because the sample was small, we did not obtain statistically significance results.
CONCLUSION
Whole-exome sequencing to screen pathogenic gene mutations was applied successfully. Although no third-gene mutation associated with HME was found, a total of nine mutations across EXT1 and EXT2 were identified, four of which are novel. Our results expand the mutational spectrum of EXT and can be used in genetic counseling and prenatal diagnosis for patients with MO.
Topics: Adolescent; Adult; Child; Exostoses, Multiple Hereditary; Female; Genotype; Humans; Male; Middle Aged; Mutation; N-Acetylglucosaminyltransferases; Exome Sequencing; Young Adult
PubMed: 32293802
DOI: 10.1111/os.12660 -
Computational and Mathematical Methods... 2022Symptomatic osteochondroma of the proximal femur necessitates a surgical excision. The purpose of this study was to describe a novel technique of computer...
PURPOSE
Symptomatic osteochondroma of the proximal femur necessitates a surgical excision. The purpose of this study was to describe a novel technique of computer navigation-aided excision for osteochondromata of the proximal femur. Outcomes of this technique are also presented.
METHODS
A total of 13 patients underwent computer navigation-aided excision of osteochondromata of the proximal femur from February 2012 to August 2016 in our institution. They were enrolled in this study. OrthoMap 3D (Stryker Orthopaedics, Mahwah, NJ, USA), a commercially available navigation software system, was used to merge computed tomography images of the proximal femur with an osteochondromata with the image of a normal proximal femur. Using the normal proximal femur as a template, intended resection margins for the proximal femur with osteochondromata were planned and then executed using intraoperative navigation guidance. Patients were followed up clinically and radiographically. The physical and mental health of patients was assessed with the Musculoskeletal Tumor Society (MSTS) score.
RESULTS
Eight patients had isolated exostoses. Five patients had tumors associated with multiple hereditary exostoses. For tumors projecting posteriorly or posteromedially, a posterolateral approach was used. For tumors projecting anteriorly or medially, an anterior approach was used. Prophylactic fixation was performed in four patients who required an anterior approach. The mean duration of the surgery was 189 minutes. There were no intraoperative fractures or postoperative complications. A secondary procedure was not needed for any case. The mean MSTS score at a mean follow-up of 17 months was 28.6 (maximum MSTS score: 30).
CONCLUSIONS
This is the first study to report a novel application of computer navigation for aiding the excision of osteochondromata of the proximal femur. It demonstrated favorable postoperative functional scores with a low rate of complications. The applicability, safety, and efficacy of this technique were demonstrated. It is particularly useful for resections involving large tumors that can obscure anatomical landmarks and for patients with associated proximal femoral deformity.
Topics: Bone Neoplasms; Computers; Femur; Humans; Osteochondroma; Retrospective Studies; Surgery, Computer-Assisted; Treatment Outcome
PubMed: 35685895
DOI: 10.1155/2022/7635945 -
BMC Musculoskeletal Disorders Jan 2021Hereditary multiple exostoses (HME) is a rare skeletal disorder characterised by a widespread. distribution of osteochondromas originating from the metaphyses of long... (Review)
Review
BACKGROUND
Hereditary multiple exostoses (HME) is a rare skeletal disorder characterised by a widespread. distribution of osteochondromas originating from the metaphyses of long bones.
CASE PRESENTATION
This case study examines a 55-year-old male cadaver bequeathed to the University of Liverpool who suffered from HME, thus providing an exceptionally rare opportunity to examine the anatomical changes associated with this condition.
CONCLUSIONS
Findings from imaging and dissection indicated that this was a severe case of HME in terms of the quantity and distribution of the osteochondromas and the number of synostoses present. In addition, the existence of enchondromas and the appearance of gaps within the trabeculae of affected bones make this a remarkable case. This study provides a comprehensive overview of the morbidity of the disease as well as adding to the growing evidence that diseases concerning benign cartilaginous tumours may be part of a spectrum rather than distinct entities.
Topics: Bone Neoplasms; Bone and Bones; Diagnostic Imaging; Exostoses, Multiple Hereditary; Humans; Male; Middle Aged; Osteochondroma
PubMed: 33478453
DOI: 10.1186/s12891-021-03967-6 -
Bone Jun 2018Multiple osteochondromas (MO) syndrome is a dominant autosomal bone disorder characterized by the formation of cartilage-capped bony outgrowths that develop at the...
Multiple osteochondromas (MO) syndrome is a dominant autosomal bone disorder characterized by the formation of cartilage-capped bony outgrowths that develop at the juxtaposition of the growth plate of endochondral bones. MO has been linked to mutations in either EXT1 or EXT2, two glycosyltransferases required for the synthesis of heparan sulfate (HS). The establishment of mouse mutants demonstrated that a clonal, homozygous loss of Ext1 in a wild type background leads to the development of osteochondromas. Here we investigate mechanisms that might contribute to the variation in the severity of the disease observed in human patients. Our results show that residual amounts of HS are sufficient to prevent the development of osteochondromas strongly supporting that loss of heterozygosity is required for osteochondroma formation. Furthermore, we demonstrate that different signaling pathways affect size and frequency of the osteochondromas thereby modulating the severity of the disease. Reduced Fgfr3 signaling, which regulates proliferation and differentiation of chondrocytes, increases osteochondroma number, while activated Fgfr3 signaling reduces osteochondroma size. Both, activation and reduction of Wnt/β-catenin signaling decrease osteochondroma size and frequency by interfering with the chondrogenic fate of the mutant cells. Reduced Ihh signaling does not change the development of the osteochondromas, while elevated Ihh signaling increases the cellularity and inhibits chondrocyte differentiation in a subset of osteochondromas and might thus predispose osteochondromas to the transformation into chondrosarcomas.
Topics: Animals; Cell Differentiation; Chondrocytes; Disease Models, Animal; Exostoses, Multiple Hereditary; Growth Plate; Hedgehog Proteins; Heparitin Sulfate; Humans; Loss of Heterozygosity; Mice; N-Acetylglucosaminyltransferases; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Wnt Signaling Pathway; beta Catenin
PubMed: 29545125
DOI: 10.1016/j.bone.2018.03.010 -
Oncology Letters Mar 2016Synovial osteochondromatosis is a rare condition in which multiple cartilaginous nodules proliferate within the synovial membranes of joints, tendon sheaths or bursae....
Synovial osteochondromatosis is a rare condition in which multiple cartilaginous nodules proliferate within the synovial membranes of joints, tendon sheaths or bursae. In general, a complete synovectomy is an effective method to treat this disease. Commonly involved joints are the knee, glenohumeral joint, elbow, hip and ankle, although any articulation may be affected. However, synovial osteochondromatosis occurs rarely in the wrist, and there have been a lack of reports of this occurrence in the literature. The current study presents a case of synovial osteochondromatosis in a 33-year-old man, who was admitted in 2014 with the symptom of swelling of the left wrist joint for 2 years. The swelling had become increasingly painful over the previous 2 months. Physical examination revealed local tenderness and a soft pliable mass, with no involvement of the skin and with moderate pain. X-ray, computed tomography and magnetic resonance imaging of the left wrist revealed a lump at the volar radial side of the left wrist joint without any bone erosion. The lesion was subsequently excised. Histological examination resulted in a diagnosis of osteochondromatosis, which was not considered prior to the surgery. The present case was reported with the aim of analyzing the clinical, imaging characteristic and therapeutic modalities of synovial osteochondromatosis of the wrist. While there was no evidence of recurrence for the subsequent 4 months of post-operative follow-up in the present case, the long-term efficacy of surgical excision requires extended observation.
PubMed: 26998083
DOI: 10.3892/ol.2016.4106 -
Molecular Cytogenetics May 2023Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony...
BACKGROUND
Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder characterized by the development of multiple, circumscript and usually symmetric bony protuberances called osteochondromas. Most HME are caused by EXT1 and EXT2 loss of function mutations. Most pathogenic mutations are nonsense followed by missense mutations and deletions.
CASE PRESENTATION
Here we report on a patient with a rare and complex genotype resulting in a typical HME phenotype. Initial point mutation screening in EXT1 and EXT2 genes by Sanger sequencing did not reveal any pathogenic variants. The patient along with the healthy parents was subsequently referred for karyotype and array-Comparative Genomic Hybridization (CGH) analyses. Chromosomal analysis revealed two independent de novo apparently balanced rearrangements: a balanced translocation between the long arms of chromosomes 2 and 3 at breakpoints 2q22 and 3q13.2 and a pericentric inversion with breakpoints at 8p23.1q24.1. Both breakpoints were confirmed by Fluorescence In Situ Hybridization (FISH). Subsequently, array-CGH revealed a novel heterozygous deletion within the EXT1 gene at one of the inversion breakpoints, rendering the inversion unbalanced. The mode of inheritance, as well as the size of the deletion were further investigated by Quantitative Real-time PCR (qPCR), defining the deletion as de novo and of 3.1 kb in size, removing exon 10 of EXT1. The inversion in combination with the 8p23.1 deletion most likely abolishes the transcription of EXT1 downstream of exon 10 hence resulting in a truncated protein.
CONCLUSIONS
The identification of a rare and novel genetic cause of HME, highlights the importance of additional comprehensive investigation of patients with typical clinical manifestations, even when EXT1 and EXT2 mutation analysis is negative.
PubMed: 37217936
DOI: 10.1186/s13039-023-00638-0 -
Expert Opinion on Orphan Drugs 2018Hereditary multiple exostoses (HME) is a rare congenital pediatric disorder characterized by osteochondromas forming next to the growth plates in young patients. The...
INTRODUCTION
Hereditary multiple exostoses (HME) is a rare congenital pediatric disorder characterized by osteochondromas forming next to the growth plates in young patients. The osteochondromas cause multiple health problems that include skeletal deformities and chronic pain. Surgery is used to remove the most symptomatic osteochondromas but because of their large number, many are left in place, causing life-long problems and increasing the probability of malignant transformation. There is no other treatment to prevent or reduce osteochondromas formation at present.
AREAS COVERED
Recent studies reviewable through PubMed are providing new insights into cellular and molecular mechanisms of osteochondroma development. The resulting data are suggesting rational and plausible new therapeutic strategies for osteochondroma prevention some of which are being tested in HME animal models and one of which is part of a just announced clinical trial.
EXPERT COMMENTARY
This section summarizes and evaluates such strategies and points also to possible future alternatives.
PubMed: 31448184
DOI: 10.1080/21678707.2018.1483232