Septal chondrocyte hypertrophy contributes to midface deformity in a mouse model of Apert syndrome.
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ABSTRACT:
SUBMITTER: Kim BS
PROVIDER: S-EPMC8041873 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:A 9-year-old male showed severe defects in midface structures, which resulted in maxillary hypoplasia, ocular hypertelorism, relative mandibular prognathism, and syndactyly. He had been diagnosed as having Apert syndrome and received a surgery of frontal calvaria distraction osteotomy to treat the steep forehead at 6 months old, and a surgery of digital separation to treat severe syndactyly of both hands at 6 years old. Nevertheless, he still showed a turribrachycephalic cranial profile with proptosis, a horizontal groove above supraorbital ridge, and a short nose with bulbous tip. Methods:Fundamental aberrant growth may be associated with the cranial base structure in radiological observation. Results:The Apert syndrome patient had a shorter and thinner nasal septum in panthomogram, PA view, and Waters' view; shorter zygomatico-maxillary width (83.5 mm) in Waters' view; shorter length between the sella and nasion (63.7 mm) on cephalogram; and bigger zygomatic axis angle of the cranial base (118.2°) in basal cranial view than a normal 9-year-old male (94.8 mm, 72.5 mm, 98.1°, respectively). On the other hand, the Apert syndrome patient showed interdigitating calcification of coronal suture similar to that of a normal 30-year-old male in a skull PA view. Conclusion:Taken together, the Apert syndrome patient, 9 years old, showed retarded growth of the anterior cranial base affecting severe midface hypoplasia, which resulted in a hypoplastic nasal septum axis, retruded zygomatic axes, and retarded growth of the maxilla and palate even after frontal calvaria distraction osteotomy 8 years ago. Therefore, it was suggested that the severe midface hypoplasia and dysostotic facial profile of the present Apert syndrome case are closely relevant to the aberrant growth of the anterior cranial base supporting the whole oro-facial and forebrain development.
| S-EPMC6289935 | biostudies-other
Project description:Apert syndrome (AS), the most severe form of craniosynostosis, is caused by missense mutations including Pro253Arg(P253R) of fibroblast growth factor receptor 2 (FGFR2), which leads to enhanced FGF/FGFR2-signaling activity. Surgical correction of the deformed skull is the typical treatment for AS. Because of constant maldevelopment of sutures, the corrective surgery is often executed several times, resulting in increased patient challenge and complications. Biological therapies targeting the signaling of mutant FGFR2 allele, in combination with surgery, may bring better outcome. Here we screened and found a small interfering RNA (siRNA) specifically targeting the Fgfr2-P253R allele, and we revealed that it inhibited osteoblastic differentiation and matrix mineralization by reducing the signaling of ERK1/2 and P38 in cultured primary calvarial cells and calvarial explants from Apert mice (Fgfr2+/P253R). Furthermore, AAV9 carrying short hairpin RNA (shRNA) (AAV9-Fgfr2-shRNA) against mutant Fgfr2 was delivered to the skulls of AS mice. Results demonstrate that AAV9-Fgfr2-shRNA attenuated the premature closure of coronal suture and the decreased calvarial bone volume of AS mice. Our study provides a novel practical biological approach, which will, in combination with other therapies, including surgeries, help treat patients with AS while providing experimental clues for the biological therapies of other genetic skeletal diseases.
| S-EPMC6197781 | biostudies-literature
Project description:Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological processes, with osteoarthritis being a prominent example. We perform a dynamic analysis of a qualitative mathematical model of the regulatory network that directs this phenotypic switch to investigate the influence of the individual factors holistically. To estimate the stability of a SOX9 positive state (associated with resting/proliferation chondrocytes) versus a RUNX2 positive one (associated with hypertrophy) we employ two measures. The robustness of the state in canalisation (size of the attractor basin) is assessed by a Monte Carlo analysis and the sensitivity to perturbations is assessed by a perturbational analysis of the attractor. Through qualitative predictions, these measures allow for an in silico screening of the effect of the modelled factors on chondrocyte maintenance and hypertrophy. We show how discrepancies between experimental data and the model's results can be resolved by evaluating the dynamic plausibility of alternative network topologies. The findings are further supported by a literature study of proposed therapeutic targets in the case of osteoarthritis.
| S-EPMC5007039 | biostudies-literature
Project description:AIMS:Cardiovascular manifestations are a major cause of mortality in Marfan syndrome (MFS). Animal models that mimic the syndrome and its clinical variability are instrumental for understanding the genesis and risk factors for cardiovascular disease in MFS. This study used morphological and ultrastructural analysis to the understanding of the development of cardiovascular phenotypes of the the mgΔloxPneo model for MFS. METHODS AND RESULTS:We studied 6-month-old female mice of the 129/Sv background, 6 wild type (WT) and 24 heterozygous animals from the mgΔloxPneo model. Descending thoracic aortic aneurysm and/or dissection (dTAAD) were identified in 75% of the MFS animals, defining two subgroups: MFS with (MFS+) and without (MFS-) dTAAD. Both subgroups showed increased fragmentation of elastic fibers, predominance of type I collagen surrounding the elastic fiber and fragmentation of interlaminar fibers when compared to WT. However, only MFS animals with spine tortuosity developed aortic aneurysm/dissection. The aorta of MFS+ animals were more tortuous compared to those of MFS- and WT mice, possibly causing perturbations of the luminal blood flow. This was evidenced by the detection of diminished aorta-blood flow in MFS+. Accordingly, only MFS+ animals presented a process of concentric cardiac hypertrophy and a significantly decreased ratio of left and right ventricle lumen area. CONCLUSIONS:We show that mgΔloxPneo model mimics the vascular disease observed in MFS patients. Furthermore, the study indicates role of thoracic spine deformity in the development of aorta diseases. We suggest that degradation of support structures of the aortic wall; deficiency in the sustenance of the thoracic vertebrae; and their compression over the adjacent aorta resulting in disturbed blood flow is a triad of factors involved in the genesis of dissection/aneurysm of thoracic aorta.
| S-EPMC6855660 | biostudies-literature
Project description:Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome patients. Although the genetic causes underlying Apert syndrome have been identified, the downstream signaling pathways and cellular mechanisms responsible for cleft palate are still elusive. To find clues for the pathogenic mechanisms of palatal defects in Apert syndrome, we review the clinical characteristics of the palate in cases of Apert syndrome, the palatal phenotypes in mouse models, and the potential signaling mechanisms involved in palatal defects. In Apert syndrome patients, cleft of the soft palate is more frequent than of the hard palate. The length of the hard palate is decreased. Cleft palate is associated most commonly with the S252W variant of FGFR2. In addition to cleft palate, high-arched palate, lateral palatal swelling, or bifid uvula are common in Apert syndrome patients. Mouse models of Apert syndrome display palatal defects, providing valuable tools to understand the underlying mechanisms. The mutations in FGFR2 causing Apert syndrome may change a signaling network in epithelial-mesenchymal interactions during palatogenesis. Understanding the pathogenic mechanisms of palatal defects in Apert syndrome may shed light on potential novel therapeutic solutions.
| S-EPMC9397066 | biostudies-literature
Project description:The frequency of 18p deletion syndrome is estimated to be ∼1/50,000 live births and is more commonly associated with certain clinical features including short stature, intellectual disability, and facial dysmorphism. Physical examination of our patient revealed a short stature, intellectual disability, facial dysmorphism (microcephaly, ptosis, epicanthus, low nasal bridge, protruding ears, long philtrum, and thin lips), and clinodactyly of the fifth finger. The peripheral karyotype was 46, XX, del (18) (p11.32p11.2). DNA microarray analysis revealed a de novo 13.9-Mb deletion at 18p11.32p.11.21. Echocardiography revealed asymmetric septal hypertrophy. Congenital cardiac abnormalities are present very rarely in this syndrome. This finding suggests that one locus or loci that play a role in cardiac development is located in this chromosomal region. Although rare, cardiac hypertrophies should be kept in mind when evaluating a patient with phenotypic anomalies and genetic results compatible with an 18p deletion syndrome.
| S-EPMC9192171 | biostudies-literature
Project description:Chondrocyte hypertrophy is the terminal step in chondrocyte differentiation and is crucial for endochondral bone formation. How signaling pathways regulate chondrocyte hypertrophic differentiation remains incompletely understood. In this study, using a Tbx18:Cre (Tbx18Cre/+) gene-deletion approach, we selectively deleted the gene for the signaling protein SMAD family member 4 (Smad4f/f ) in the limbs of mice. We found that the Smad4-deficient mice develop a prominent shortened limb, with decreased expression of chondrocyte differentiation markers, including Col2a1 and Acan, in the humerus at mid-to-late gestation. The most striking defects in these mice were the absence of stylopod elements and failure of chondrocyte hypertrophy in the humerus. Moreover, expression levels of the chondrocyte hypertrophy-related markers Col10a1 and Panx3 were significantly decreased. Of note, we also observed that the expression of runt-related transcription factor 2 (Runx2), a critical mediator of chondrocyte hypertrophy, was also down-regulated in Smad4-deficient limbs. To determine how the skeletal defects arose in the mouse mutants, we performed RNA-Seq with ChIP-Seq analyses and found that Smad4 directly binds to regulatory elements in the Runx2 promoter. Our results suggest a new mechanism whereby Smad4 controls chondrocyte hypertrophy by up-regulating Runx2 expression during skeletal development. The regulatory mechanism involving Smad4-mediated Runx2 activation uncovered here provides critical insights into bone development and pathogenesis of chondrodysplasia.
| S-EPMC6005452 | biostudies-literature
Project description:Apert syndrome is a congenital disorder characterized by severe skull malformations and caused by one of two missense mutations, S252W and P253R, on fibroblast growth factor receptor 2 (FGFR2). The molecular bases underlying differential Apert syndrome phenotypes are still poorly understood and it is unclear why cleft palate is more frequent in patients carrying the S252W mutation. Taking advantage of Apert syndrome mouse models, we performed a novel combination of morphometric, histological and immunohistochemical analyses to precisely quantify distinct palatal phenotypes in Fgfr2(+/S252W) and Fgfr2(+/P253R) mice. We localized regions of differentially altered FGF signaling and assessed local cell patterns to establish a baseline for understanding the differential effects of these two Fgfr2 mutations. Palatal suture scoring and comparative 3D shape analysis from high resolution ?CT images of 120 newborn mouse skulls showed that Fgfr2(+/S252W) mice display relatively more severe palate dysmorphologies, with contracted and more separated palatal shelves, a greater tendency to fuse the maxillary-palatine sutures and aberrant development of the inter-premaxillary suture. These palatal defects are associated with suture-specific patterns of abnormal cellular proliferation, differentiation and apoptosis. The posterior region of the developing palate emerges as a potential target for therapeutic strategies in clinical management of cleft palate in Apert syndrome patients.
| S-EPMC3634659 | biostudies-literature
Project description:During the development of the appendicular skeleton, the cartilaginous templates undergo hypertrophic differentiation and remodels into bone, except for the cartilage most adjacent to joint cavities where hypertrophic differentiation and endochondral bone formation are prevented, and chondrocytes instead form articular cartilage. The mechanisms that prevent hypertrophic differentiation and endochondral bone formation of the articular cartilage have not been elucidated. To explore the role of the synovial microenvironment in chondrocyte differentiation, osteochondral allografts consisting of articular cartilage, epiphyseal bone, and growth plate cartilage from distal femoral epiphyses of inbred Lewis rats expressing enhanced green fluorescent protein from a ubiquitous promoter were transplanted either in inverted or original (control) orientation to matching sites in wildtype littermates, thereby allowing for tracing of transplanted cells and their progenies. We found that no hypertrophic differentiation occurred in the growth plate cartilage ectopically placed at the joint surface. Instead, the transplanted growth plate cartilage, with time, remodeled into articular cartilage. This finding suggests that the microenvironment at the articular surface inhibits hypertrophic differentiation and supports articular cartilage formation. To explore this hypothesis, rat chondrocyte pellets were cultured with and without synoviocyte-conditioned media. Consistent with the hypothesis, hypertrophic differentiation was inhibited and expression of the articular surface marker lubricin (Prg4) was dramatically induced when chondrocyte pellets were exposed to synovium- or synoviocyte-conditioned media, but not to chondrocyte- or osteoblast-conditioned media. Taken together, we present evidence for a novel mechanism by which synoviocytes, through the secretion of a factor or factors, act directly on chondrocytes to inhibit hypertrophic differentiation and endochondral bone formation and promote articular cartilage formation. This mechanism may have important implications for articular cartilage development, maintenance, and regeneration.
| S-EPMC9481641 | biostudies-literature
Project description:BackgroundBasal septal hypertrophy (BSH) is an asymmetric, localized thickening of the upper interventricular septum and constitutes a marker of an early remodelling in patients with hypertension. This morphological trait has been extensively researched because of its prevalence in hypertension, yet its clinical and prognostic value for individual patients remains undetermined. One of the reasons is the lack of a reliable and reproducible metric to quantify the presence and the extent of BSH. This article proposes the use of the curvature of the left ventricular endocardium as a robust feature for BSH characterization, and as an objective criterion to quantify current subjective 'visual assessment' of the presence of sigmoidal septum. The proposed marker, called average septal curvature, is defined as the inverse of the radius adjacent to each point of the endocardial contour along the basal and mid inferoseptal segments of the left ventricle.MethodRobustness and reproducibility were assessed on a cohort of 220 patients, including 161 hypertensive patients (32 with BSH) and 59 healthy controls.ResultsThe results show that compared with the conventionally used wall thickness metrics, the new marker is more reproducible (relative standard deviation of errors of 7 vs. 13%, and 8 vs. 38% for intra-observer and inter-observer variability, respectively) and better correlates to the functional parameters related to BSH, with main difference (absolute rank correlation 0.417 vs. 0.341) in local deformation changes assessed by longitudinal strain.ConclusionAverage septal curvature is a more precisely defined and reproducible metric than thickness ratios, it can be fully automated, and better infers the functional remodelling related to hypertension.
| S-EPMC8183485 | biostudies-literature