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Matthew L Speltz - One of the best experts on this subject based on the ideXlab platform.
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longitudinal analysis of parenting stress in mothers and fathers of infants with and without single suture Craniosynostosis
The Cleft Palate-Craniofacial Journal, 2015Co-Authors: Kristen E Gray, Brent R Collett, Kathleen A Kappsimon, Mary Michaeleen Cradock, Lynette D Pullmann, Matthew L SpeltzAbstract:Objective: To examine longitudinal differences in reported stress between parents of children with and without single-suture Craniosynostosis and to compare the stress reports of mothers and fathers. Design: Multi-site, nonrandomized prospective study. Setting/Participants: Children with single-suture Craniosynostosis (cases) were identified via referral of the treating surgeon or physician at the time of diagnosis, and those without single-suture Craniosynostosis (controls) were recruited from pediatric practices, birthing centers, and announcements in print media. When children were aged 6, 18, and 36 months (on average), mothers and fathers of children with and without single-suture Craniosynostosis completed the Parenting Stress Index. For cases, 247 mothers and 211 fathers completed the Parenting Stress Index at the first visit; corresponding numbers for controls were 254 and 220, respectively. Main Outcome Measures: The Parenting Stress Index Parent and Child Domains and subscales scores. Results: W...
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multicenter study of neurodevelopment in 3 year old children with and without single suture Craniosynostosis
JAMA Pediatrics, 2012Co-Authors: Jacqueline R Starr, Michael L Cunningham, Brent R Collett, Rebecca Gaither, Kathleen A Kappsimon, Mary Michaeleen Cradock, Matthew L SpeltzAbstract:Objective To evaluate the hypothesis that 3-year-old children with single-suture Craniosynostosis would receive lower neurodevelopmental scores than a comparable group of children born with patent sutures. Design Longitudinal comparison study. Setting Five tertiary care craniofacial centers. Participants Patients with Craniosynostosis (cases) and a comparison group of children without Craniosynostosis (controls). Patients diagnosed with single-suture Craniosynostosis from 2002 to 2006 were eligible as cases. Controls were frequency-matched to cases on age, sex, race, socioeconomic status, and study site. Main Exposure Craniosynostosis. Main Outcome Measures We administered the Bayley Scales of Infant Development, Second Edition, mental and motor development indices and the Preschool Language Scales, Third Edition, receptive and expressive communication scales. Children were evaluated at baseline (before surgery in cases and at a similar age in controls) and at 18 and 36 months of age. We compared the groups' performances at 36 months by fitting adjusted linear and logistic regression models. We also estimated adjusted associations between age at surgery and neurodevelopmental scores. Results Adjusted mean case deficits ranged from 3 to 6 points (P ≤ .008 for all comparisons). Compared with controls, the odds of cases being delayed ranged from 1.5 to 2.0, depending on the neurodevelopmental scale (P values ranged from .03 to .09). Cases' ages at Craniosynostosis repair were not strongly related to neurodevelopmental performance. Conclusions In this large, carefully controlled, multicenter study, we observed consistently lower mean neurodevelopmental scores in children with single-suture Craniosynostosis compared with controls. These results provide further support for neurodevelopmental screening in young children with single-suture Craniosynostosis.
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copy number variation analysis in single suture Craniosynostosis multiple rare variants including runx2 duplication in two cousins with metopic Craniosynostosis
American Journal of Medical Genetics Part A, 2010Co-Authors: H C Mefford, Anne V. Hing, Neil Shafer, Francesca Antonacci, Jesse Tsai, Sarah S Park, Mark J Rieder, Matthew D Smyth, Matthew L SpeltzAbstract:Little is known about genes that underlie isolated single-suture Craniosynostosis. In this study, we hypothesize that rare copy number variants (CNV) in patients with isolated single-suture Craniosynostosis contain genes important for cranial development. Using whole genome array comparative genomic hybridization (CGH), we evaluated DNA from 186 individuals with single-suture Craniosynostosis for submicroscopic deletions and duplications. We identified a 1.1 Mb duplication encompassing RUNX2 in two affected cousins with metopic synostosis and hypodontia. Given that RUNX2 is required as a master switch for osteoblast differentiation and interacts with TWIST1, mutations in which also cause Craniosynostosis, we conclude that the duplication in this family is pathogenic, albeit with reduced penetrance. In addition, we find that a total of 7.5% of individuals with single-suture synostosis in our series have at least one rare deletion or duplication that contains genes and that has not been previously reported in unaffected individuals. The genes within and disrupted by CNVs in this cohort are potential novel candidate genes for Craniosynostosis.
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single suture Craniosynostosis a review of neurobehavioral research and theory
Journal of Pediatric Psychology, 2004Co-Authors: Matthew L Speltz, Michael L Cunningham, Kathleen A Kappsimon, Jeffrey L Marsh, Geraldine DawsonAbstract:Objective To review research and theory regarding the neurobehavioral correlates and outcomes of single-suture, or isolated, Craniosynostosis in children. Methods A critical review of 17 studies of the hypothesized association between isolated Craniosynostosis and neurodevelopment. Results Isolated Craniosynostosis is associated with a three- to fivefold increase in risk for cognitive deficits or learning/language disabilities. The causal basis for this association is unclear. No particular calvarial suture (sagittal, metopic, left or right unilateral coronal) has been associated with higher risk of problems. There is little evidence from quasi-experimental studies that cranioplastic surgery prevents or reduces risk of neurobehavioral impairment. Conclusions Future studies would benefit from larger samples and larger control groups; measures of specific neuropsychological functions (in addition to global cognition); analyses of neuropsychological status in relation to the severity and cortical impact of synostosis; and an examination of interactions between synostosis and social/family risk factors on neurodevelopment. Routine neurodevelopmental screening of young children with isolated Craniosynostosis is recommended.
Michael T Longaker - One of the best experts on this subject based on the ideXlab platform.
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skeletal stem and progenitor cells maintain cranial suture patency and prevent Craniosynostosis
Nature Communications, 2021Co-Authors: Siddharth Menon, Bjorn Behr, Michael Januszyk, Ankit Salhotra, Siny Shailendra, Ruth Tevlin, Ryan C Ransom, Charles Chan, Derrick C Wan, Michael T LongakerAbstract:Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called Craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cells derived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2LacZ/+ mouse, endowing enhanced Wnt activation, to a Twist1+/- mouse model of coronal Craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1+/- mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie Craniosynostosis. These findings have translational implications toward therapeutic approaches for Craniosynostosis.
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Craniosynostosis of coronal suture in twist1 mice occurs through endochondral ossification recapitulating the physiological closure of posterior frontal suture
Frontiers in Physiology, 2011Co-Authors: Bjorn Behr, Michael T Longaker, Natalina QuartoAbstract:Craniosynostosis, the premature closure of cranial suture, is a pathologic condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic condition characterized by Craniosynostosis. The Saethre-Chotzen syndrome, which is defined by loss-of-function mutations in the TWIST gene, is the second most prevalent Craniosynostosis. Although much of the genetics and phenotypes in Craniosynostosis syndromes is understood, less is known about the underlying ossification mechanism during suture closure. We have previously demonstrated that physiological closure of the posterior frontal (PF) suture occurs through endochondral ossification. Moreover, we revealed that antagonizing canonical Wnt signaling in the sagittal suture leads to endochondral ossification of the suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the haploinsufficient Twist1+/- mice represents a suitable model for studying this syndrome. Thus, we seeked to understand the underlying ossification process in coronal Craniosynostosis in Twist1+/- mice. Our data indicate that coronal suture closure in Twist1+/- mice occurs between postnatal day 9 to 13 by endochondral ossification, as shown by histology, gene expression analysis and immunohistochemistry. In conclusion, this study reveals that coronal Craniosynostosis in Twist1+/- mice occurs through endochondral ossification. Moreover, it suggests that haploinsufficency of Twist1 gene, a target of canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of inactive canonical Wnt-signaling leading to Craniosynostosis.
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the bmp antagonist noggin regulates cranial suture fusion
Nature, 2003Co-Authors: Stephen M Warren, Lisa J Brunet, Richard M. Harland, Aris N Economides, Michael T LongakerAbstract:During skull development, the cranial connective tissue framework undergoes intramembranous ossification to form skull bones (calvaria). As the calvarial bones advance to envelop the brain, fibrous sutures form between the calvarial plates1. Expansion of the brain is coupled with calvarial growth through a series of tissue interactions within the cranial suture complex2. Craniosynostosis, or premature cranial suture fusion, results in an abnormal skull shape, blindness and mental retardation3. Recent studies have demonstrated that gain-of-function mutations in fibroblast growth factor receptors (fgfr) are associated with syndromic forms of Craniosynostosis4,5. Noggin, an antagonist of bone morphogenetic proteins (BMPs), is required for embryonic neural tube, somites and skeleton patterning6,7,8. Here we show that noggin is expressed postnatally in the suture mesenchyme of patent, but not fusing, cranial sutures, and that noggin expression is suppressed by FGF2 and syndromic fgfr signalling. Since noggin misexpression prevents cranial suture fusion in vitro and in vivo, we suggest that syndromic fgfr-mediated craniosynostoses may be the result of inappropriate downregulation of noggin expression.
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studies in cranial suture biology up regulation of transforming growth factor beta1 and basic fibroblast growth factor mrna correlates with posterior frontal cranial suture fusion in the rat
Plastic and Reconstructive Surgery, 1998Co-Authors: Daniel Most, Joanne Sung, James Chang, Stephen A. Schendel, Joseph G. Mccarthy, Jamie P. Levine, Michael T LongakerAbstract:The mechanisms involved in normal cranial suture development and fusion as well as in the pathophysiology of craniosyostosis are not well understood. The purpose of this study was to investigate the expression of several cytokines—transforming growth factor-beta-1 (TGF-β1), basic fibroblast growth factor (bFGF), and interleukin-6 (IL-6)—during cranial suture fusion. TGF-β exists in three mammalian isoforms that are abundant in bone and stimulate calvarial bone formation when delivered locally. Other bone growth factors including basic fibroblast growth factor and the interleukins regulate bone growth and are mitogenic for bone marrow cells and osteoblasts. The involvement of growth factors in the pathophysiology of Craniosynostosis is supported by recent genetics data linking fibroblast growth factor receptor mutations to syndromal craniosynostoses. In this experimental study, in situ hybridization was used to localize and quantify the gene expression of TGF-β1, bFGF, and IL-6 during cranial suture fusion. In the Sprague-Dawley rat, the posterior frontal cranial suture normally undergoes fusion between 12 and 22 days of age, whereas all other cranial sutures remain patent. All in situ analyses of fusing posterior frontal sutures were compared with the patent, control, sagittal sutures. Posterior frontal and sagittal sutures, together with underlying dura, were harvested from rats at 8, 12, 16, and 35 days of postnatal life to analyze posterior frontal suture activity before, during, and after fusion. In situ hybridization was performed on frozen sections of these specimens using DNA probes specific for TGF-β1, bFGF, and IL-6 mRNA. A negative control probe to IL-6 in the sense orientation was also used to validate the procedure. Cells expressing cytokine-specific mRNA were quantified (in cells positive per 10-1 mm2) and analyzed using the unpaired Student's t test. Areas encompassing the fibrous suture and the surrounding bone plates were analyzed for cellular mRNA activity. IL-6 mRNA expression showed a minimal rise in the posterior frontal suture at days 12 and 16, with an average count of 10 and 6 cells per 10-1 mm2, respectively. The sagittal suture remained negative for IL-6 mRNA at all time points. TGF-β1 and bFGF analyses were most interesting, showing marked increases specifically in the posterior frontal suture during the time of active suture fusion. On postnatal day 8, a 1.5-fold increase in posterior frontal suture TGF-β1 mRNA was found compared with sagittal sutures (p = 0.1890, unpaired Student's t test). This difference was increased 26-fold on day 12 in posterior frontal suture TGF-β1 expression (p = 0.0005). By day 35, posterior frontal suture TGF-β1 mRNA had nearly returned to prefusion levels, whereas TGF-β1 mRNA levels in the sagittal suture remained low. A similar upregulation of bFGF mRNA, peaking at day 12, was observed in posterior frontal but not sagittal sutures (p = 0.0003). Furthermore, both TGF-β1 and bFGF mRNA samples with intact dura showed an intense dural mRNA expression in the time preceding and during active posterior frontal suture fusion but not in sagittal tissues. Our data demonstrate that TGF-β1 and bFGF mRNA are up-regulated in cranial suture fusion, possibly signaling in a paracrine fashion from dura to suture. TGF-β1 and bFGF gene expression were dramatically increased both in and surrounding the actively fusing suture and followed the direction of fusion from endocranial to epicranial. These experimental data on bone growth factors support the recent human genetics data linking growth factor/fibroblast growth factor receptor deletions to syndromal craniosynostoses. The ultimate aim of these studies is to understand the underlying mechanisms regulating suture growth, development, and fusion so surgeons may one day manipulate the biology of premature cranial suture fusion. (Plast. Reconstr. Surg. 101: 1431, 1998.)
Nan E Hatch - One of the best experts on this subject based on the ideXlab platform.
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viral delivery of tissue nonspecific alkaline phosphatase diminishes Craniosynostosis in one of two fgfr2c342y mouse models of crouzon syndrome
PLOS ONE, 2020Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Iva Vesela, Nan E HatchAbstract:Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset Craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset Craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished Craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on Craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes Craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.
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viral delivery of tissue nonspecific alkaline phosphatase diminishes Craniosynostosis in one of two fgfr2c342y mouse models of crouzon syndrome
bioRxiv, 2020Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Iva Vesela, Nan E HatchAbstract:Abstract Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset Craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset Craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro computed tomography. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished Craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p
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tissue nonspecific alkaline phosphatase improves bone quality but does not alleviate Craniosynostosis in the fgfr2c342y mouse model of crouzon syndrome
bioRxiv, 2019Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Nan E HatchAbstract:Crouzon syndrome is a congenital disorder characterized by Craniosynostosis, the premature fusion of cranial bones. Craniosynostosis leads to high intracranial pressure and abnormal skull and facial shapes that are relieved by surgery. Crouzon syndrome is caused by activating mutations in fibroblast growth factor receptor 2 (FGFR2). The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in post-natal Craniosynostosis onset BALB/c and/or peri-natal Craniosynostosis onset C57BL/6 FGFR2C342Y/+ mouse models of Crouzon syndrome. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro computed tomography. Craniofacial shape was measured with calipers using previously established landmarks and measurements. Alkaline phosphatase activity levels were measured in serum. Results show that postnatal delivery of TNAP increases serum levels of alkaline phosphatase activity and improves bone volume, density and mineral content, but does not alleviate Craniosynostosis, craniofacial shape or cranial base abnormalities in FGFR2C342Y/+ Crouzon mice. These results indicate that post-natal recombinant TNAP enzyme therapy is therapeutic for bone mineralization but not efficacious for relief of FGFR-associated Craniosynostosis and associated craniofacial shape defects.
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tissue nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the alpl mouse model of infantile hypophosphatasia
Bone, 2014Co-Authors: Jin Liu, Hwa Kyung Nam, Cassie Campbell, Kellen Cristina Da Silva Gasque, Jose Luis Millan, Nan E HatchAbstract:Abstract Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how Craniosynostosis develops in these disorders is unknown. Objectives Because Craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated Craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior–posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony Craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote Craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base.
Alessandro Consales - One of the best experts on this subject based on the ideXlab platform.
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Pure Bilateral Lambdoid and Posterior Sagittal Synostosis (Mercedes-Benz Syndrome): Case Report and Literature Review.
World neurosurgery, 2019Co-Authors: Alberto Balestrino, Francesca Secci, Gianluca Piatelli, Giovanni Morana, Marco Pavanello, Mattia Pacetti, Armando Cama, Alessandro ConsalesAbstract:Background Bilateral lambdoid and posterior sagittal synostosis is a rarely encountered multisutural Craniosynostosis accounting for 0.3%−0.7% of all craniosynostoses. It has been named “Mercedes−Benz Syndrome” (MBS) because of the bone ridges that resemble the Mercedes−Benz logo. The typical head shape is usually described as anterior turricephaly combined with mild brachycephaly. We describe a case of pure MBS without involvement of other sutures. Since we believe that MBS is a different pathology when other sutures are involved, we will discuss our case with a review of the literature, including all reported cases of bilateral lambdoid and posterior sagittal synostosis with no other sutures involved but sagittal and bilateral lambdoid. Case Description A 3-month-old female baby came to our attention because of a turrycephalic appearance of the head. Findings of the neurologic examination were unremarkable. Computed tomography scan showed premature fusion of posterior third of sagittal suture and bilateral lambdoid suture. Magnetic resonance imaging did not show relevant intracranial abnormalities. She underwent sagittal decompression extended posteriorly below the lambdoid suture combined with biparietal decompression to obtain expansion of both parieto-frontal bones and posterior fossa. Post-operative course was uneventful. Follow-up at 3 months showed a good aesthetic result, and results of the neurologic examination were unremarkable. Conclusions Pure MBS is a rare condition that unlike other multisutural complex Craniosynostosis is rarely associated with genetic syndromes, has a low rate of associated intracranial anomalies, and has less need for more skull-remodeling surgery. The choice of the most suitable surgical procedure must be tailored on the patient, considering preoperative head appearance and eventually associated anomalies.
Hwa Kyung Nam - One of the best experts on this subject based on the ideXlab platform.
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viral delivery of tissue nonspecific alkaline phosphatase diminishes Craniosynostosis in one of two fgfr2c342y mouse models of crouzon syndrome
PLOS ONE, 2020Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Iva Vesela, Nan E HatchAbstract:Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset Craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset Craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro CT. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished Craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p<0.02) and the incidence of malocclusion from 82.4% to 34.7% (p<0.03), with no effect on cranial bone in C57BL/6 FGFR2C342Y/+ mice. In contrast, treatment with TNAP increased cranial bone volume (p< 0.01), density (p< 0.01) and mineral content (p< 0.01) as compared to vehicle treated controls, but had no effect on Craniosynostosis or malocclusion in BALB/c FGFR2C342Y/+ mice. These results indicate that postnatal recombinant TNAP enzyme therapy diminishes Craniosynostosis severity in the C57BL/6 FGFR2C342Y/+ neonatal onset mouse model of Crouzon syndrome, and that effects of exogenous TNAP are genetic background dependent.
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viral delivery of tissue nonspecific alkaline phosphatase diminishes Craniosynostosis in one of two fgfr2c342y mouse models of crouzon syndrome
bioRxiv, 2020Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Iva Vesela, Nan E HatchAbstract:Abstract Craniosynostosis is the premature fusion of cranial bones. The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in a C57BL/6 FGFR2C342Y/+ model of neonatal onset Craniosynostosis or a BALB/c FGFR2C342Y/+ model of postnatal onset Craniosynostosis. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro computed tomography. Craniofacial shape was measured with calipers. Alkaline phosphatase, alanine amino transferase (ALT) and aspartate amino transferase (AST) activity levels were measured in serum. Neonatal delivery of TNAP diminished Craniosynostosis severity from 94% suture obliteration in vehicle treated mice to 67% suture obliteration in treated mice, p
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tissue nonspecific alkaline phosphatase improves bone quality but does not alleviate Craniosynostosis in the fgfr2c342y mouse model of crouzon syndrome
bioRxiv, 2019Co-Authors: Hwa Kyung Nam, Sara Dean Schutte, Nan E HatchAbstract:Crouzon syndrome is a congenital disorder characterized by Craniosynostosis, the premature fusion of cranial bones. Craniosynostosis leads to high intracranial pressure and abnormal skull and facial shapes that are relieved by surgery. Crouzon syndrome is caused by activating mutations in fibroblast growth factor receptor 2 (FGFR2). The goal of this study was to determine if delivery of recombinant tissue nonspecific alkaline phosphatase (TNAP) could prevent or diminish the severity of Craniosynostosis in post-natal Craniosynostosis onset BALB/c and/or peri-natal Craniosynostosis onset C57BL/6 FGFR2C342Y/+ mouse models of Crouzon syndrome. Mice were injected with a lentivirus encoding a mineral targeted form of TNAP immediately after birth. Cranial bone fusion as well as cranial bone volume, mineral content and density were assessed by micro computed tomography. Craniofacial shape was measured with calipers using previously established landmarks and measurements. Alkaline phosphatase activity levels were measured in serum. Results show that postnatal delivery of TNAP increases serum levels of alkaline phosphatase activity and improves bone volume, density and mineral content, but does not alleviate Craniosynostosis, craniofacial shape or cranial base abnormalities in FGFR2C342Y/+ Crouzon mice. These results indicate that post-natal recombinant TNAP enzyme therapy is therapeutic for bone mineralization but not efficacious for relief of FGFR-associated Craniosynostosis and associated craniofacial shape defects.
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tissue nonspecific alkaline phosphatase deficiency causes abnormal craniofacial bone development in the alpl mouse model of infantile hypophosphatasia
Bone, 2014Co-Authors: Jin Liu, Hwa Kyung Nam, Cassie Campbell, Kellen Cristina Da Silva Gasque, Jose Luis Millan, Nan E HatchAbstract:Abstract Tissue-nonspecific alkaline phosphatase (TNAP) is an enzyme present on the surface of mineralizing cells and their derived matrix vesicles that promotes hydroxyapatite crystal growth. Hypophosphatasia (HPP) is an inborn-error-of-metabolism that, dependent upon age of onset, features rickets or osteomalacia due to loss-of function mutations in the gene (Alpl) encoding TNAP. Craniosynostosis is prevalent in infants with HPP and other forms of rachitic disease but how Craniosynostosis develops in these disorders is unknown. Objectives Because Craniosynostosis carries high morbidity, we are investigating craniofacial skeletal abnormalities in Alpl−/− mice to establish these mice as a model of HPP-associated Craniosynostosis and determine mechanisms by which TNAP influences craniofacial skeletal development. Methods Cranial bone, cranial suture and cranial base abnormalities were analyzed by micro-CT and histology. Craniofacial shape abnormalities were quantified using digital calipers. TNAP expression was suppressed in MC3T3E1(C4) calvarial cells by TNAP-specific shRNA. Cells were analyzed for changes in mineralization, gene expression, proliferation, apoptosis, matrix deposition and cell adhesion. Results Alpl−/− mice feature craniofacial shape abnormalities suggestive of limited anterior–posterior growth. Craniosynostosis in the form of bony coronal suture fusion is present by three weeks after birth. Alpl−/− mice also exhibit marked histologic abnormalities of calvarial bones and the cranial base involving growth plates, cortical and trabecular bone within two weeks of birth. Analysis of calvarial cells in which TNAP expression was suppressed by shRNA indicates that TNAP deficiency promotes aberrant osteoblastic gene expression, diminished matrix deposition, diminished proliferation, increased apoptosis and increased cell adhesion. Conclusions These findings demonstrate that Alpl−/− mice exhibit a craniofacial skeletal phenotype similar to that seen in infants with HPP, including true bony Craniosynostosis in the context of severely diminished bone mineralization. Future studies will be required to determine if TNAP deficiency and other forms of rickets promote Craniosynostosis directly through abnormal calvarial cell behavior, or indirectly due to deficient growth of the cranial base.