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Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis.

ABSTRACT: Normal extension and skull expansion is a synchronized process that prevails along the osteogenic intersections of the cranial sutures. Cranial sutures operate as bone growth sites allowing swift bone generation at the edges of the bone fronts while they remain patent. Premature fusion of one or more cranial sutures can trigger craniosynostosis, a birth defect characterized by dramatic manifestations in appearance and functional impairment. Up until today, surgical correction is the only restorative measure for craniosynostosis associated with considerable mortality. Clinical studies have identified several genes implicated in the pathogenesis of craniosynostosis syndromes with useful insights into the underlying molecular signaling events that determine suture fate. In this review, we exploit the intracellular signal transduction pathways implicated in suture pathobiology, in an attempt to identify key signaling molecules for therapeutic targeting.

SUBMITTER: Katsianou MA

PROVIDER: S-EPMC5144105 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis.

Katsianou Maria A MA Adamopoulos Christos C Vastardis Heleni H Basdra Efthimia K EK

BBA clinical 20160429

Normal extension and skull expansion is a synchronized process that prevails along the osteogenic intersections of the cranial sutures. Cranial sutures operate as bone growth sites allowing swift bone generation at the edges of the bone fronts while they remain patent. Premature fusion of one or more cranial sutures can trigger craniosynostosis, a birth defect characterized by dramatic manifestations in appearance and functional impairment. Up until today, surgical correction is the only restora ...[more]

PMID: 27957430

Similar Datasets

Gene expression changes between patent and fused cranial sutures in a nonsyndromic craniosynostosis population.

Project description:ObjectiveCraniosynostosis is a premature fusion of 1 or more cranial sutures. It may occur with additional morphological abnormalities (syndromic) or in isolation. Studies suggest that dysregulation of normal cell proliferation, differentiation, and migration has a role in isolated or nonsyndromic craniosynostosis but the molecular mechanisms remain unknown. The aim of this research is to identify genes differentially expressed in prematurely fused human suture compared to patent suture in nonsyndromic craniosynostosis.MethodsBone fragments from synostosed and patent sutures of 7 infants with nonsyndromic craniosynostosis were collected during surgical release of fused sutures. RNA was isolated from the fragments (7 patent and 7 fused) and global gene expression profiled using the Illumina WGE-DASL assay and HumanRef 8.0 Beadchip.ResultsComparison of mRNA expression in fused and patent suture identified 68 genes significantly differentially expressed and having fold changes ≤ -2.0 and ≥ 2.0 with a false discovery rate adjusted P value at .10 and 136 with adjusted P value of 0.15. SFRP2 (secreted frizzled-related protein 2) demonstrated the largest decrease in fused sutures. Analysis including only sagittal fused sutures revealed a set of 35 overlapping genes that may be involved in suture patency over all suture types. SPHKAP (sphingosine kinase type 1-interacting protein), a modulator of TGFβ signaling, was significant in the sagittal subset.ConclusionDifferentially expressed genes were identified in fused suture relative to patent in a nonsyndromic craniosynostosis population. SFRP2 is likely important in suture patency. Genes having significant roles in osteoblastogenesis as negative regulators of canonical Wnt pathway were significantly downregulated.

| S-EPMC4401998 | biostudies-literature

Gene Expression Changes Between Patent and Fused Cranial Sutures in a Nonsyndromic Craniosynostosis Population

Project description:Assaying gene expression in sutural bone fragments from patients diagnosed with non-syndromic craniosynostosis. Sutural fragments were collected from both the fused and patent cranial suture of infants during cranial vault reconstruction. Gene expression was compared between the patent and fused sutures using the paired t-test. The aim was to identify thoses genes significantly differentially expressed in fused suture relative to patent.

2013-09-12 | GSE50796 | GEO

Gene Expression Changes Between Patent and Fused Cranial Sutures in a Nonsyndromic Craniosynostosis Population

2013-09-12 | E-GEOD-50796 | biostudies-arrayexpress

BMP9 induces osteogenesis and adipogenesis in the immortalized human cranial suture progenitors from the patent sutures of craniosynostosis patients.

Project description:The cranial suture complex is a heterogeneous tissue consisting of osteogenic progenitor cells and mesenchymal stem cells (MSCs) from bone marrow and suture mesenchyme. The fusion of cranial sutures is a highly coordinated and tightly regulated process during development. Craniosynostosis is a congenital malformation caused by premature fusion of cranial sutures. While the progenitor cells derived from the cranial suture complex should prove valuable for studying the molecular mechanisms underlying suture development and pathogenic premature suture fusion, primary human cranial suture progenitors (SuPs) have limited life span and gradually lose osteoblastic ability over passages. To overcome technical challenges in maintaining sufficient and long-term culture of SuPs for suture biology studies, we establish and characterize the reversibly immortalized human cranial suture progenitors (iSuPs). Using a reversible immortalization system expressing SV40 T flanked with FRT sites, we demonstrate that primary human suture progenitor cells derived from the patent sutures of craniosynostosis patients can be efficiently immortalized. The iSuPs maintain long-term proliferative activity, express most of the consensus MSC markers and can differentiate into osteogenic and adipogenic lineages upon BMP9 stimulation in vitro and in vivo. The removal of SV40 T antigen by FLP recombinase results in a decrease in cell proliferation and an increase in the endogenous osteogenic and adipogenic capability in the iSuPs. Therefore, the iSuPs should be a valuable resource to study suture development, intramembranous ossification and the pathogenesis of craniosynostosis, as well as to explore cranial bone tissue engineering.

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Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis.

Project description:Craniosynostosis is a bone developmental disease where premature ossification of the cranial sutures occurs leading to fused sutures. While biomechanical forces have been implicated in craniosynostosis, evidence of the effect of microenvironmental stiffness changes in the osteogenic commitment of cells from the sutures is lacking. Our aim was to identify the differential genetic expression and osteogenic capability between cells from patent and fused sutures of children with craniosynostosis and whether these differences are driven by changes in the stiffness of the microenvironment. Cells from both sutures demonstrated enhanced mineralisation with increasing substrate stiffness showing that stiffness is a stimulus capable of triggering the accelerated osteogenic commitment of the cells from patent to fused stages. The differences in the mechanoresponse of these cells were further investigated with a PCR array showing stiffness-dependent upregulation of genes mediating growth and bone development (TSHZ2, IGF1), involved in the breakdown of extracellular matrix (MMP9), mediating the activation of inflammation (IL1?) and controlling osteogenic differentiation (WIF1, BMP6, NOX1) in cells from fused sutures. In summary, this study indicates that stiffer substrates lead to greater osteogenic commitment and accelerated bone formation, suggesting that stiffening of the extracellular environment may trigger the premature ossification of the sutures.

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The Morphogenesis of Cranial Sutures in Zebrafish.

Project description:Using morphological, histological, and TEM analyses of the cranium, we provide a detailed description of bone and suture growth in zebrafish. Based on expression patterns and localization, we identified osteoblasts at different degrees of maturation. Our data confirm that, unlike in humans, zebrafish cranial sutures maintain lifelong patency to sustain skull growth. The cranial vault develops in a coordinated manner resulting in a structure that protects the brain. The zebrafish cranial roof parallels that of higher vertebrates and contains five major bones: one pair of frontal bones, one pair of parietal bones, and the supraoccipital bone. Parietal and frontal bones are formed by intramembranous ossification within a layer of mesenchyme positioned between the dermal mesenchyme and meninges surrounding the brain. The supraoccipital bone has an endochondral origin. Cranial bones are separated by connective tissue with a distinctive architecture of osteogenic cells and collagen fibrils. Here we show RNA in situ hybridization for col1a1a, col2a1a, col10a1, bglap/osteocalcin, fgfr1a, fgfr1b, fgfr2, fgfr3, foxq1, twist2, twist3, runx2a, runx2b, sp7/osterix, and spp1/ osteopontin, indicating that the expression of genes involved in suture development in mammals is preserved in zebrafish. We also present methods for examining the cranium and its sutures, which permit the study of the mechanisms involved in suture patency as well as their pathological obliteration. The model we develop has implications for the study of human disorders, including craniosynostosis, which affects 1 in 2,500 live births.

| S-EPMC5102434 | biostudies-literature

Growth of cranial synchondroses and sutures requires polycystin-1.

Project description:In vertebrates, coordinated embryonic and postnatal growth of the craniofacial bones and the skull base is essential during the expansion of the rostrum and the brain. Identification of molecules that regulate skull growth is important for understanding the nature of craniofacial defects and for development of non-invasive biologically based diagnostics and therapies. Here we report on spatially restricted growth defects at the skull base and in craniofacial sutures of mice deficient for polycystin-1 (Pkd1). Mutant animals reveal a premature closure of both presphenoid and sphenooccipital synchondroses at the cranial base. Furthermore, knockout mice lacking Pkd1 in neural crest cells are characterized by impaired postnatal growth at the osteogenic fronts in craniofacial sutures that are subjected to tensile forces. Our data suggest that polycystin-1 is required for proliferation of subpopulations of cranial osteochondroprogenitor cells of both mesodermal and neural crest origin during skull growth. However, the Erk1/2 signalling pathway is up-regulated in the Pkd1-deficient skeletal tissue, similarly to that previously reported for polycystic kidney.

| S-EPMC2576296 | biostudies-literature

Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis.

Project description:Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

| S-EPMC8306115 | biostudies-literature

3D pediatric cranial bone imaging using high-resolution MRI for visualizing cranial sutures: a pilot study.

Project description:ObjectiveThere is an unmet need to perform imaging in young children and obtain CT-equivalent cranial bone images without subjecting the patients to radiation. In this study, the authors propose using a high-resolution fast low-angle shot golden-angle 3D stack-of-stars radial volumetric interpolated breath-hold examination (GA-VIBE) MRI sequence that is intrinsically robust to motion and has enhanced bone versus soft-tissue contrast.MethodsPatients younger than 11 years of age, who underwent clinical head CT scanning for craniosynostosis or other cranial malformations, were eligible for the study. 3D reconstructed images created from the GA-VIBE MRI sequence and the gold-standard CT scan were randomized and presented to 3 blinded reviewers. For all image sets, each reviewer noted the presence or absence of the 6 primary cranial sutures and recorded on 5-point Likert scales whether they recommended a second scan be performed.ResultsEleven patients (median age 1.8 years) underwent MRI after clinical head CT scanning was performed. Five of the 11 patients were sedated. Three clinicians reviewed the images, and there were no cases, either with CT scans or MR images, in which a reviewer agreed a repeat scan was required for diagnosis or surgical planning. The reviewers reported clear imaging of the regions of interest on 99% of the CT reviews and 96% of the MRI reviews. With CT as the standard, the sensitivity and specificity of the GA-VIBE MRI sequence to detect suture closure were 97% and 96%, respectively (n = 198 sutures read).ConclusionsThe 3D reconstructed images using the GA-VIBE sequence in comparison to the CT scans created clinically acceptable cranial images capable of detecting cranial sutures. Future directions include reducing the scan time, improving motion correction, and automating postprocessing for clinical utility.

| S-EPMC7736460 | biostudies-literature

Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis.

Project description:Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.

| S-EPMC7891303 | biostudies-literature

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