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Michael T. Longaker - One of the best experts on this subject based on the ideXlab platform.
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Confocal laser scanning microscopic analysis of collagen scaffolding patterns in Cranial Sutures.
Journal of Craniofacial Surgery, 2020Co-Authors: Stephen M. Warren, Michael T. Longaker, Benjamin Walder, Kang TingAbstract:Although recent studies indicate that regional dura mater influences the fate of the overlying Cranial Suture, little is known about the assembly of extracellular matrix (ECM) molecules within the patent and fusing murine Cranial Suture complexes. Confocal laser scanning microscopy was used to study ECM assembly within patent and fusing Cranial Suture complexes. Coronal sections (20 μm thick) of patent sagittal (SAG) and fusing posterior frontal (PF) Sutures from postnatal 8-, 14-, and 18-day-old Sprague-Dawley rats were scanned in 0.5-μm increments, and images were collected consecutively to create a z-series for three-dimensional reconstruction. Spatial and temporal collagen arrangements were compared between SAG and PF Sutures by measuring interfiber distance, fiber thickness, and total collagen surface area at each time point. We demonstrate that on day 8 (before the onset of Suture fusion), collagen bundles are randomly arranged in both the SAG and PF Sutures. By day 14 (midfusion period), there was a statistically significant reduction in total collagen surface area (80.5% versus 67.4%; P < 0.05) as the collagen bundles were organized into orthogonal lattices along the anterior and endoCranial margins of the PF Suture. Furthermore, new bone matrix deposition was observed along the edges of these organized collagen bundles. In contrast, collagen within the SAG Suture remained randomly arranged and unossified. By day 18 (late fusion period), the PF Suture was completely fused except for the posterior-ectoCranial portion. This patent section of the PF Suture contained a highly organized mineralizing orthogonal collagen lattice. The total collagen surface area in the day-18 PF Suture continued to decline compared with the day-8 PF Suture (80.5% versus 55.6%; P < 0.05). In the day-18 SAG Suture, the collagen bundles remained randomly arranged, and the total surface area did not change. The same analysis was performed in a human pathologic fusing and patent Suture. Similar results were observed. The total collagen surface area significantly decreased in the pathologic fusing human Suture compared with the patent Suture (92.8% versus 60.6%; P < 0.05). Moreover, the pathologically fusing Suture contained a highly organized mineralizing orthogonal collagen lattice. This is the first analysis of collagen patterns in patent and fusing Cranial Sutures.
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Cranial Suture Biology
Current Topics in Developmental Biology, 2020Co-Authors: Kelly A. Lenton, Randall P. Nacamuli, Jill A. Helms, Michael T. LongakerAbstract:Publisher Summary This chapter focuses on the Cranial Suture biology. The term “craniosynostosis” was first used in 1830 by Otto to describe the premature fusion of Cranial Sutures. Since this first identification of craniosynostosis as a distinct clinical entity, several theories have been proposed to explain both the pathogenesis of premature Suture fusion and the resultant aberrations in calvarial growth that result in a dysmorphic skull. Recent advances in clinical genetics have resulted in the identification of genetic mutations in the major craniosynostostic syndromes. Despite these insights into the rudimentary disturbances leading to craniosynostosis, the processes by which mutations in these genes trigger premature Suture fusion remain largely unknown. Rodents are proving to be extremely valuable in unraveling the cellular and molecular mechanisms of Cranial Suture morphogenesis and pathology. The Cranial Sutures include the metopic or interfrontal Suture (between the frontal bones), the sagittal Suture (between the parietal bones), the coronal Suture (between the frontal and parietal bones), and the lambdoid Sutures (between the parietal and interparietal bones). The Sutures can be thought of as a complex consisting of four principal components: (1) the osteogenic fronts of the approximating bone plates; (2) the Suture mesenchyme spanning the osteogenic fronts; (3) the overlying pericranium or Cranial periosteum; and (4) the underlying dura mater, a tough, fibrous membrane that constitutes the outer meningeal layer that envelops the brain and forms the inner lining of Cranial bones and Sutures. The main objective is to obtain a thorough understanding of normal and pathological Suture morphogenesis and development. Armed with this knowledge, researchers will be prepared to devise biologically based therapeutic strategies that could be used both in utero or postnatally to prevent craniosynostosis, potentially alleviating any adverse sequelae and avoiding the morbidity of current surgical approaches.
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models of Cranial Suture biology
Journal of Craniofacial Surgery, 2012Co-Authors: Monica Grova, David Lo, Daniel T Montoro, Jeong S Hyun, Michael T Chung, Michael T. LongakerAbstract:Craniosynostosis is a common congenital defect caused by premature fusion of Cranial Sutures. The severe morphological abnormalities and cognitive deficits resulting from craniosynostosis and the potential morbidity of surgical correction espouse the need for a deeper understanding of the complex etiology for this condition. Work in animal models over the past twenty years has been pivotal in advancing our understanding of normal Suture biology and elucidating pathological disease mechanisms. This article provides an overview of milestone studies in Suture development, embryonic origins, and signaling mechanisms from an array of animal models including transgenic mice, rats, rabbits, fetal sheep, zebrafish, and frogs. This work contributes to an ongoing effort toward continued development of novel treatment strategies.
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Cranial Suture biology from pathways to patient care
Journal of Craniofacial Surgery, 2012Co-Authors: Benjamin Levi, Victor W Wong, Emily R Nelson, Jeong Hyun, Michael T. LongakerAbstract:AbstractCraniosynostosis describes the premature pathologic partial or complete fusion of 1 or more of the Cranial Sutures. Over the past few decades, research on craniosynostosis has progressed from gross description of deformities to an understanding of some of the molecular etiologies behind prem
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paracrine interaction between adipose derived stromal cells and Cranial Suture derived mesenchymal cells
Plastic and Reconstructive Surgery, 2010Co-Authors: Aaron W James, Benjamin Levi, George W Commons, Jason P Glotzbach, Michael T. LongakerAbstract:Introduction Adipose derived stromal cells (ASCs) are a potential cell source for the successful healing of skeletal defects. In this study we sought to investigate the potential for Cranial Suture-derived mesenchymal cells (SMCs) to promote the osteogenic differentiation of ASCs. Various reports have previously examined the unique in vitro attributes of SMCs; this study sought to extend those findings.
Jamie P Levine - One of the best experts on this subject based on the ideXlab platform.
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Growth restriction of Cranial Sutures in the fetal lamb causes deformational changes, not craniosynostosis.
Plastic and Reconstructive Surgery, 2000Co-Authors: James P. Bradley, Hrayr Shahinian, Norman M. Rowe, Jamie P Levine, Michael T. LongakerAbstract:Newborns with in utero Cranial vault molding can present with severe forms of plagiocephaly. Intrauterine constraint has been proposed as one cause for craniosynostosis. The purpose of this experiment was to investigate whether rigid plate fixation across a fetal Cranial Suture, representing a severe form of growth restriction in utero, would lead to Cranial Suture fusion in a fetal lamb model. Six fetal lambs at 85 to 95 days gestation (term = 145 days) underwent laparotomy, hysterotomy, fetal coronal scalp incision, and miniplate screw fixation across the right coronal Suture in utero. Two unoperated twins and four unoperated age-matched lambs were used as controls (n = 12). Animals were killed at both 4 and 8 weeks postoperatively. Fetal head analysis consisted of gross examination, photography, basilar and lateral radiographs, and three-dimensional computed tomographic scans. Cranial Suture analysis consisted of imaging by computed tomographic scan (axial and sagittal cuts) and histology of experimentally plated coronal Sutures, contralateral nonplated coronal Sutures and twin control coronal Sutures. Gross examination, radiographs, and three-dimensional computed tomographic analysis of heads with Cranial Suture plating showed ipsilateral forehead flattening, contralateral forehead bossing, superiorly displaced ipsilateral orbital rim, anterolateral projection of ipsilateral malar eminence, and anterior position of the ipsilateral ear point compared with the contralateral side of the same animal and normal controls. There was no change in nasal root, chin point, or predentition occlusal plane. Although analysis of the plated coronal Sutures by computed tomographic scans showed diminished width or even stenosis, the histology revealed narrowed but patent experimental coronal Sutures at 4 and 8 weeks. Contralateral, nonplated coronal Sutures were not only patent, but widened compared with normal control Sutures. This finding may have represented compensatory changes in the contralateral coronal Suture caused by growth restriction at the plated Suture. These data demonstrate that intrauterine growth restriction across a Cranial Suture caused by compression plate fixation resulted in deformational skull changes, not craniosynostosis. In addition, these data strongly support a role for in utero positional molding secondary to growth restriction in the maternal pelvis as a cause for nonsynostotic plagiocephaly seen in newborns.
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increased igf i and igf ii mrna and igf i peptide in fusing rat Cranial Sutures suggest evidence for a paracrine role of insulin like growth factors in Suture fusion
Plastic and Reconstructive Surgery, 1999Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:Premature Cranial Suture fusion, or craniosynostosis, can result in gross aberrations of craniofacial growth. The biology underlying Cranial Suture fusion remains poorly understood. Previous studies of the Sprague-Dawley rat posterior frontal Suture, which fuses at between 12 and 20 days, have sugge
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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, Jamie P Levine, Joseph G Mccarthy, Joanne Sung, James Chang, Stephen A Schendel, 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.)
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studies in Cranial Suture biology regional dura mater determines overlying Suture biology
Plastic and Reconstructive Surgery, 1998Co-Authors: Jamie P Levine, James P. Bradley, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:The influence of dura mater on adjacent Cranial Sutures is significant. By better understanding the mechanisms of normal Suture fusion and the role of the dura mater, it may be possible to delineate the events responsible for the premature Suture fusion seen in craniosynostosis. In the Sprague-Dawley rat, the posterior frontal Suture normally fuses between 12 and 20 days of postnatal life and has proved to be an excellent model to describe normal Suture fusion. The purpose of this study was to document the critical role that the dura mater-Suture complex may play on Cranial Suture biology. Forty Sprague-Dawley rats at 8 days of age were divided into two groups of 20 animals each. The control group (group A) had surgical disruption of the dura mater-calvarial interface. This was accomplished by elevating a strip of cranium inclusive of the posterior frontal and sagittal Sutures and replacement of the Cranial strip back to its anatomic position, all with the dura mater left intact. The experimental group (group B) had the same calvarial elevation (strip craniectomy), but the sutural anatomy/ alignment was rotated 180 degrees. This rotation placed the posterior frontal Suture into the sagittal Suture's anatomic position and the sagittal Suture into the posterior frontal Suture's anatomic position. All of these procedures were accomplished by leaving the underlying dura mater intact. Animals were killed at 20, 30, 40, and 50 days (12, 22, 32, and 42 days postoperatively), and tissue sections were examined with hematoxylin and eosin staining. Group A (control) showed normal but delayed Suture activity. The posterior frontal Suture fused, and the sagittal Suture remained patent. Fusion was delayed, not beginning before 20 days (12 days postoperative) and showing complete fusion between 30 and 40 days. Group B (180-degree calvarial rotation) demonstrated that the Suture in the posterior frontal anatomic position (actual sagittal Suture) fused between 20 and 40 days, whereas the Suture in the sagittal anatomic position (actual posterior-frontal Suture) remained patent throughout the study. This study demonstrates that the location of the dura mater-Suture complex is important in determining either Suture patency or closure in this model. Normal closure of the Suture overlying the posterior frontal dura mater demonstrates that the dura mater itself, or forces derived in specific Cranial locations, determines the overlying Suture biology.
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studies in Cranial Suture biology regional dura mater determines in vitro Cranial Suture fusion
Plastic and Reconstructive Surgery, 1997Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Michael T. LongakerAbstract:: Craniosynostosis results in alterations in craniofacial growth that create cosmetic abnormalities and functional deficits, yet the biology underlying Cranial Suture fusion remains unknown. The purpose of the present study was to show that regional dura mater can induce Suture fusion while in an organ culture system in Cranial Sutures programmed to remain patient. To accomplish this, we studied mouse Cranial Sutures, since in this model the posterior frontal Suture (analogous to the human metopic Suture) fuses in both in vivo and in vitro environments while all other Sutures remain patent. We demonstrated that when mouse sagittal Sutures (programmed to remain patent) were rotated or translocated to overlie the posterior frontal dura then grown in organ culture systems, Suture fusion occurred. Twenty-four-day-old CD-1 mice (time when the posterior frontal Suture was patent) were divided into three groups of 50 (n = 165: three groups of 50 cultured and three groups of 5 uncultured controls). Group A (unrotated control group) was characterized by a strip of posterior frontal and sagittal Suture with underlying dural tissue grown in organ culture systems for up to 30 days and resulted in persistent patency of the sagittal Suture and fusion of the posterior frontal Suture in an anterior-to-posterior direction. Group B (rotated experimental group) was characterized by 180-degree Suture rotation while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in a posterior-to-anterior Suture direction. Group C (translocated experimental group) was characterized by translocation or shifting of Sutures while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in an anterior-to-posterior Suture direction. These data from the in vitro rotation and translocation experiments indicate that the "regional" posterior frontal dura determined in vitro Cranial Suture fusion. Molecular mechanisms behind this process are thought to involve inductive tissue interactions of the dural cells with the Suture cells by means of growth factor-mediated signal pathways.
Joseph G Mccarthy - One of the best experts on this subject based on the ideXlab platform.
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increased igf i and igf ii mrna and igf i peptide in fusing rat Cranial Sutures suggest evidence for a paracrine role of insulin like growth factors in Suture fusion
Plastic and Reconstructive Surgery, 1999Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:Premature Cranial Suture fusion, or craniosynostosis, can result in gross aberrations of craniofacial growth. The biology underlying Cranial Suture fusion remains poorly understood. Previous studies of the Sprague-Dawley rat posterior frontal Suture, which fuses at between 12 and 20 days, have sugge
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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, Jamie P Levine, Joseph G Mccarthy, Joanne Sung, James Chang, Stephen A Schendel, 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.)
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studies in Cranial Suture biology regional dura mater determines overlying Suture biology
Plastic and Reconstructive Surgery, 1998Co-Authors: Jamie P Levine, James P. Bradley, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:The influence of dura mater on adjacent Cranial Sutures is significant. By better understanding the mechanisms of normal Suture fusion and the role of the dura mater, it may be possible to delineate the events responsible for the premature Suture fusion seen in craniosynostosis. In the Sprague-Dawley rat, the posterior frontal Suture normally fuses between 12 and 20 days of postnatal life and has proved to be an excellent model to describe normal Suture fusion. The purpose of this study was to document the critical role that the dura mater-Suture complex may play on Cranial Suture biology. Forty Sprague-Dawley rats at 8 days of age were divided into two groups of 20 animals each. The control group (group A) had surgical disruption of the dura mater-calvarial interface. This was accomplished by elevating a strip of cranium inclusive of the posterior frontal and sagittal Sutures and replacement of the Cranial strip back to its anatomic position, all with the dura mater left intact. The experimental group (group B) had the same calvarial elevation (strip craniectomy), but the sutural anatomy/ alignment was rotated 180 degrees. This rotation placed the posterior frontal Suture into the sagittal Suture's anatomic position and the sagittal Suture into the posterior frontal Suture's anatomic position. All of these procedures were accomplished by leaving the underlying dura mater intact. Animals were killed at 20, 30, 40, and 50 days (12, 22, 32, and 42 days postoperatively), and tissue sections were examined with hematoxylin and eosin staining. Group A (control) showed normal but delayed Suture activity. The posterior frontal Suture fused, and the sagittal Suture remained patent. Fusion was delayed, not beginning before 20 days (12 days postoperative) and showing complete fusion between 30 and 40 days. Group B (180-degree calvarial rotation) demonstrated that the Suture in the posterior frontal anatomic position (actual sagittal Suture) fused between 20 and 40 days, whereas the Suture in the sagittal anatomic position (actual posterior-frontal Suture) remained patent throughout the study. This study demonstrates that the location of the dura mater-Suture complex is important in determining either Suture patency or closure in this model. Normal closure of the Suture overlying the posterior frontal dura mater demonstrates that the dura mater itself, or forces derived in specific Cranial locations, determines the overlying Suture biology.
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studies in Cranial Suture biology regional dura mater determines in vitro Cranial Suture fusion
Plastic and Reconstructive Surgery, 1997Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Michael T. LongakerAbstract:: Craniosynostosis results in alterations in craniofacial growth that create cosmetic abnormalities and functional deficits, yet the biology underlying Cranial Suture fusion remains unknown. The purpose of the present study was to show that regional dura mater can induce Suture fusion while in an organ culture system in Cranial Sutures programmed to remain patient. To accomplish this, we studied mouse Cranial Sutures, since in this model the posterior frontal Suture (analogous to the human metopic Suture) fuses in both in vivo and in vitro environments while all other Sutures remain patent. We demonstrated that when mouse sagittal Sutures (programmed to remain patent) were rotated or translocated to overlie the posterior frontal dura then grown in organ culture systems, Suture fusion occurred. Twenty-four-day-old CD-1 mice (time when the posterior frontal Suture was patent) were divided into three groups of 50 (n = 165: three groups of 50 cultured and three groups of 5 uncultured controls). Group A (unrotated control group) was characterized by a strip of posterior frontal and sagittal Suture with underlying dural tissue grown in organ culture systems for up to 30 days and resulted in persistent patency of the sagittal Suture and fusion of the posterior frontal Suture in an anterior-to-posterior direction. Group B (rotated experimental group) was characterized by 180-degree Suture rotation while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in a posterior-to-anterior Suture direction. Group C (translocated experimental group) was characterized by translocation or shifting of Sutures while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in an anterior-to-posterior Suture direction. These data from the in vitro rotation and translocation experiments indicate that the "regional" posterior frontal dura determined in vitro Cranial Suture fusion. Molecular mechanisms behind this process are thought to involve inductive tissue interactions of the dural cells with the Suture cells by means of growth factor-mediated signal pathways.
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studies in Cranial Suture biology part i increased immunoreactivity for tgf β isoforms β1 β2 and β3 during rat Cranial Suture fusion
Journal of Bone and Mineral Research, 1997Co-Authors: Douglas A Roth, Jamie P Levine, Michael T. Longaker, Joseph G Mccarthy, Heather Mcmullen, David M Rosen, Joanne Sung, Leslie I GoldAbstract:The mechanisms involved in normal Cranial Suture development and fusion as well as the pathophysiology of craniosynostosis, a premature fusion of the Cranial Sutures, are not well understood. Transforming growth factor-β isoforms (TGF-β1, β2, and β3) are abundant in bone and stimulate calvarial bone formation when injected locally in vivo. To gain insight into the role of these factors in normal growth and development of Cranial Sutures and the possible etiology of premature Cranial Suture fusion, we examined the temporal and spatial expression of TGF-β isoforms during normal Cranial Suture development in the rat. In the Sprague-Dawley rat, only the posterior frontal Cranial Suture undergoes fusion between 12 and 22 days of age, while all other Cranial Sutures remain patent. Therefore, immunohistochemical analysis of the fusing posterior frontal Suture was compared with the patent sagittal Suture at multiple time points from the fetus through adult. Whereas the intensity of immunostaining was the same in the posterior frontal and sagittal Sutures in the fetal rat, there was increased immunoreactivity for TGF-β isoforms in the actively fusing posterior frontal Suture compared with the patent sagittal Suture starting 2 days after birth and continuing until approximately 20 days. There were intensely immunoreactive osteoblasts present during fusion of the posterior frontal Suture. In contrast, the patent sagittal Suture was only slightly immunoreactive. A differential immunostaining pattern was observed among the TGF-β isoforms; TGF-β2 was the most immunoreactive isoform and was also most strongly associated with osteoblasts adjacent to the dura and the margin of the fusing Suture. Since the increased expression of TGF-β2 during Suture fusion suggested a possible regulatory role, recombinant TGF-β2 was added directly to the posterior frontal and sagittal Sutures in vivo to determine if Suture fusion could be initiated. Exogenously added TGF-β2 stimulated fusion of the ectoCranial surface of the posterior frontal Suture. These data provide evidence for a regulatory role for these growth factors in Cranial Suture development and fusion. Additionally, the intense immunostaining for TGF-β2 in the dura mater underlying the fusing Suture supports a role for the dura mater in Suture fusion. It is possible that premature or excessive expression of these factors may be involved in the etiopathogenesis of craniosynostosis and that modulation of the growth factor profile at the Suture site may have potential therapeutic value.
James P. Bradley - One of the best experts on this subject based on the ideXlab platform.
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Cranial Suture response to stress expression patterns of noggin and runx2
Plastic and Reconstructive Surgery, 2007Co-Authors: Justin B Heller, Joubin S Gabbay, Kristy L Wasson, Scott Mitchell, Misha M Heller, James P. BradleyAbstract:Background: Current theory on normal Cranial Suture fusion entrusts the dura with the regulatory role. Studies suggest that the dura responds to stress with changes in gene expression. Noggin (bone morphogenetic protein inhibitor) expression is decreased in normal (rat and mouse) Cranial Suture fusion, but its role in craniosynostosis and the response to stress has not been studied. Methods: Posterior frontal (fusing) and sagittal (patent) rat Cranial Sutures were held static, oscillated, or distracted for 10 days in an organ culture microdistraction device beginning at 5 days of age (n = 30 Sutures, or 10 Sutures per group). The percentage of fusion equaled the score received for bony closure. Noggin, Runx2, and alkaline phosphatase expression was localized by immunohistochemistry for all groups. Results: Both the posterior frontal and sagittal Sutures demonstrated a significant (p < 0.05) increase in fusion percentage with oscillation relative to the static control. Noggin was not expressed in the fusing posterior frontal Suture but was expressed in the normally patent sagittal Suture. Conversely, Runx2 was expressed in the posterior frontal Suture but not in the sagittal Suture. However, when a mechanical stress was applied, both the posterior frontal and sagittal Sutures expressed Runx2 but not Noggin, as in the static fusing Suture. Conclusions: The application of mechanical stress to Cranial Sutures results in fusion of both the posterior frontal Suture and the normally patent sagittal Suture. Runx2 is expressed but Noggin is not expressed. Thus, mechanical stress influences sutural fusion and may play a role in craniosynostosis. (Plast.
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Growth restriction of Cranial Sutures in the fetal lamb causes deformational changes, not craniosynostosis.
Plastic and Reconstructive Surgery, 2000Co-Authors: James P. Bradley, Hrayr Shahinian, Norman M. Rowe, Jamie P Levine, Michael T. LongakerAbstract:Newborns with in utero Cranial vault molding can present with severe forms of plagiocephaly. Intrauterine constraint has been proposed as one cause for craniosynostosis. The purpose of this experiment was to investigate whether rigid plate fixation across a fetal Cranial Suture, representing a severe form of growth restriction in utero, would lead to Cranial Suture fusion in a fetal lamb model. Six fetal lambs at 85 to 95 days gestation (term = 145 days) underwent laparotomy, hysterotomy, fetal coronal scalp incision, and miniplate screw fixation across the right coronal Suture in utero. Two unoperated twins and four unoperated age-matched lambs were used as controls (n = 12). Animals were killed at both 4 and 8 weeks postoperatively. Fetal head analysis consisted of gross examination, photography, basilar and lateral radiographs, and three-dimensional computed tomographic scans. Cranial Suture analysis consisted of imaging by computed tomographic scan (axial and sagittal cuts) and histology of experimentally plated coronal Sutures, contralateral nonplated coronal Sutures and twin control coronal Sutures. Gross examination, radiographs, and three-dimensional computed tomographic analysis of heads with Cranial Suture plating showed ipsilateral forehead flattening, contralateral forehead bossing, superiorly displaced ipsilateral orbital rim, anterolateral projection of ipsilateral malar eminence, and anterior position of the ipsilateral ear point compared with the contralateral side of the same animal and normal controls. There was no change in nasal root, chin point, or predentition occlusal plane. Although analysis of the plated coronal Sutures by computed tomographic scans showed diminished width or even stenosis, the histology revealed narrowed but patent experimental coronal Sutures at 4 and 8 weeks. Contralateral, nonplated coronal Sutures were not only patent, but widened compared with normal control Sutures. This finding may have represented compensatory changes in the contralateral coronal Suture caused by growth restriction at the plated Suture. These data demonstrate that intrauterine growth restriction across a Cranial Suture caused by compression plate fixation resulted in deformational skull changes, not craniosynostosis. In addition, these data strongly support a role for in utero positional molding secondary to growth restriction in the maternal pelvis as a cause for nonsynostotic plagiocephaly seen in newborns.
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increased igf i and igf ii mrna and igf i peptide in fusing rat Cranial Sutures suggest evidence for a paracrine role of insulin like growth factors in Suture fusion
Plastic and Reconstructive Surgery, 1999Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:Premature Cranial Suture fusion, or craniosynostosis, can result in gross aberrations of craniofacial growth. The biology underlying Cranial Suture fusion remains poorly understood. Previous studies of the Sprague-Dawley rat posterior frontal Suture, which fuses at between 12 and 20 days, have sugge
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studies in Cranial Suture biology regional dura mater determines overlying Suture biology
Plastic and Reconstructive Surgery, 1998Co-Authors: Jamie P Levine, James P. Bradley, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:The influence of dura mater on adjacent Cranial Sutures is significant. By better understanding the mechanisms of normal Suture fusion and the role of the dura mater, it may be possible to delineate the events responsible for the premature Suture fusion seen in craniosynostosis. In the Sprague-Dawley rat, the posterior frontal Suture normally fuses between 12 and 20 days of postnatal life and has proved to be an excellent model to describe normal Suture fusion. The purpose of this study was to document the critical role that the dura mater-Suture complex may play on Cranial Suture biology. Forty Sprague-Dawley rats at 8 days of age were divided into two groups of 20 animals each. The control group (group A) had surgical disruption of the dura mater-calvarial interface. This was accomplished by elevating a strip of cranium inclusive of the posterior frontal and sagittal Sutures and replacement of the Cranial strip back to its anatomic position, all with the dura mater left intact. The experimental group (group B) had the same calvarial elevation (strip craniectomy), but the sutural anatomy/ alignment was rotated 180 degrees. This rotation placed the posterior frontal Suture into the sagittal Suture's anatomic position and the sagittal Suture into the posterior frontal Suture's anatomic position. All of these procedures were accomplished by leaving the underlying dura mater intact. Animals were killed at 20, 30, 40, and 50 days (12, 22, 32, and 42 days postoperatively), and tissue sections were examined with hematoxylin and eosin staining. Group A (control) showed normal but delayed Suture activity. The posterior frontal Suture fused, and the sagittal Suture remained patent. Fusion was delayed, not beginning before 20 days (12 days postoperative) and showing complete fusion between 30 and 40 days. Group B (180-degree calvarial rotation) demonstrated that the Suture in the posterior frontal anatomic position (actual sagittal Suture) fused between 20 and 40 days, whereas the Suture in the sagittal anatomic position (actual posterior-frontal Suture) remained patent throughout the study. This study demonstrates that the location of the dura mater-Suture complex is important in determining either Suture patency or closure in this model. Normal closure of the Suture overlying the posterior frontal dura mater demonstrates that the dura mater itself, or forces derived in specific Cranial locations, determines the overlying Suture biology.
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studies in Cranial Suture biology regional dura mater determines in vitro Cranial Suture fusion
Plastic and Reconstructive Surgery, 1997Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Michael T. LongakerAbstract:: Craniosynostosis results in alterations in craniofacial growth that create cosmetic abnormalities and functional deficits, yet the biology underlying Cranial Suture fusion remains unknown. The purpose of the present study was to show that regional dura mater can induce Suture fusion while in an organ culture system in Cranial Sutures programmed to remain patient. To accomplish this, we studied mouse Cranial Sutures, since in this model the posterior frontal Suture (analogous to the human metopic Suture) fuses in both in vivo and in vitro environments while all other Sutures remain patent. We demonstrated that when mouse sagittal Sutures (programmed to remain patent) were rotated or translocated to overlie the posterior frontal dura then grown in organ culture systems, Suture fusion occurred. Twenty-four-day-old CD-1 mice (time when the posterior frontal Suture was patent) were divided into three groups of 50 (n = 165: three groups of 50 cultured and three groups of 5 uncultured controls). Group A (unrotated control group) was characterized by a strip of posterior frontal and sagittal Suture with underlying dural tissue grown in organ culture systems for up to 30 days and resulted in persistent patency of the sagittal Suture and fusion of the posterior frontal Suture in an anterior-to-posterior direction. Group B (rotated experimental group) was characterized by 180-degree Suture rotation while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in a posterior-to-anterior Suture direction. Group C (translocated experimental group) was characterized by translocation or shifting of Sutures while in vitro and resulted in patency of the posterior frontal Suture over the sagittal dura and fusion of the sagittal Suture over the posterior frontal dura in an anterior-to-posterior Suture direction. These data from the in vitro rotation and translocation experiments indicate that the "regional" posterior frontal dura determined in vitro Cranial Suture fusion. Molecular mechanisms behind this process are thought to involve inductive tissue interactions of the dural cells with the Suture cells by means of growth factor-mediated signal pathways.
Douglas A Roth - One of the best experts on this subject based on the ideXlab platform.
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increased igf i and igf ii mrna and igf i peptide in fusing rat Cranial Sutures suggest evidence for a paracrine role of insulin like growth factors in Suture fusion
Plastic and Reconstructive Surgery, 1999Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:Premature Cranial Suture fusion, or craniosynostosis, can result in gross aberrations of craniofacial growth. The biology underlying Cranial Suture fusion remains poorly understood. Previous studies of the Sprague-Dawley rat posterior frontal Suture, which fuses at between 12 and 20 days, have sugge
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studies in Cranial Suture biology regional dura mater determines overlying Suture biology
Plastic and Reconstructive Surgery, 1998Co-Authors: Jamie P Levine, James P. Bradley, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:The influence of dura mater on adjacent Cranial Sutures is significant. By better understanding the mechanisms of normal Suture fusion and the role of the dura mater, it may be possible to delineate the events responsible for the premature Suture fusion seen in craniosynostosis. In the Sprague-Dawley rat, the posterior frontal Suture normally fuses between 12 and 20 days of postnatal life and has proved to be an excellent model to describe normal Suture fusion. The purpose of this study was to document the critical role that the dura mater-Suture complex may play on Cranial Suture biology. Forty Sprague-Dawley rats at 8 days of age were divided into two groups of 20 animals each. The control group (group A) had surgical disruption of the dura mater-calvarial interface. This was accomplished by elevating a strip of cranium inclusive of the posterior frontal and sagittal Sutures and replacement of the Cranial strip back to its anatomic position, all with the dura mater left intact. The experimental group (group B) had the same calvarial elevation (strip craniectomy), but the sutural anatomy/ alignment was rotated 180 degrees. This rotation placed the posterior frontal Suture into the sagittal Suture's anatomic position and the sagittal Suture into the posterior frontal Suture's anatomic position. All of these procedures were accomplished by leaving the underlying dura mater intact. Animals were killed at 20, 30, 40, and 50 days (12, 22, 32, and 42 days postoperatively), and tissue sections were examined with hematoxylin and eosin staining. Group A (control) showed normal but delayed Suture activity. The posterior frontal Suture fused, and the sagittal Suture remained patent. Fusion was delayed, not beginning before 20 days (12 days postoperative) and showing complete fusion between 30 and 40 days. Group B (180-degree calvarial rotation) demonstrated that the Suture in the posterior frontal anatomic position (actual sagittal Suture) fused between 20 and 40 days, whereas the Suture in the sagittal anatomic position (actual posterior-frontal Suture) remained patent throughout the study. This study demonstrates that the location of the dura mater-Suture complex is important in determining either Suture patency or closure in this model. Normal closure of the Suture overlying the posterior frontal dura mater demonstrates that the dura mater itself, or forces derived in specific Cranial locations, determines the overlying Suture biology.
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studies in Cranial Suture biology part i increased immunoreactivity for tgf β isoforms β1 β2 and β3 during rat Cranial Suture fusion
Journal of Bone and Mineral Research, 1997Co-Authors: Douglas A Roth, Jamie P Levine, Michael T. Longaker, Joseph G Mccarthy, Heather Mcmullen, David M Rosen, Joanne Sung, Leslie I GoldAbstract:The mechanisms involved in normal Cranial Suture development and fusion as well as the pathophysiology of craniosynostosis, a premature fusion of the Cranial Sutures, are not well understood. Transforming growth factor-β isoforms (TGF-β1, β2, and β3) are abundant in bone and stimulate calvarial bone formation when injected locally in vivo. To gain insight into the role of these factors in normal growth and development of Cranial Sutures and the possible etiology of premature Cranial Suture fusion, we examined the temporal and spatial expression of TGF-β isoforms during normal Cranial Suture development in the rat. In the Sprague-Dawley rat, only the posterior frontal Cranial Suture undergoes fusion between 12 and 22 days of age, while all other Cranial Sutures remain patent. Therefore, immunohistochemical analysis of the fusing posterior frontal Suture was compared with the patent sagittal Suture at multiple time points from the fetus through adult. Whereas the intensity of immunostaining was the same in the posterior frontal and sagittal Sutures in the fetal rat, there was increased immunoreactivity for TGF-β isoforms in the actively fusing posterior frontal Suture compared with the patent sagittal Suture starting 2 days after birth and continuing until approximately 20 days. There were intensely immunoreactive osteoblasts present during fusion of the posterior frontal Suture. In contrast, the patent sagittal Suture was only slightly immunoreactive. A differential immunostaining pattern was observed among the TGF-β isoforms; TGF-β2 was the most immunoreactive isoform and was also most strongly associated with osteoblasts adjacent to the dura and the margin of the fusing Suture. Since the increased expression of TGF-β2 during Suture fusion suggested a possible regulatory role, recombinant TGF-β2 was added directly to the posterior frontal and sagittal Sutures in vivo to determine if Suture fusion could be initiated. Exogenously added TGF-β2 stimulated fusion of the ectoCranial surface of the posterior frontal Suture. These data provide evidence for a regulatory role for these growth factors in Cranial Suture development and fusion. Additionally, the intense immunostaining for TGF-β2 in the dura mater underlying the fusing Suture supports a role for the dura mater in Suture fusion. It is possible that premature or excessive expression of these factors may be involved in the etiopathogenesis of craniosynostosis and that modulation of the growth factor profile at the Suture site may have potential therapeutic value.
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Studies in Cranial Suture Biology: Part I. Increased Immunoreactivity for TGF‐β Isoforms (β1, β2, and β3) During Rat Cranial Suture Fusion
Journal of Bone and Mineral Research, 1997Co-Authors: Douglas A Roth, Jamie P Levine, Michael T. Longaker, Joseph G Mccarthy, David M Rosen, Joanne Sung, Heather F. Mcmullen, Leslie I GoldAbstract:The mechanisms involved in normal Cranial Suture development and fusion as well as the pathophysiology of craniosynostosis, a premature fusion of the Cranial Sutures, are not well understood. Transforming growth factor-β isoforms (TGF-β1, β2, and β3) are abundant in bone and stimulate calvarial bone formation when injected locally in vivo. To gain insight into the role of these factors in normal growth and development of Cranial Sutures and the possible etiology of premature Cranial Suture fusion, we examined the temporal and spatial expression of TGF-β isoforms during normal Cranial Suture development in the rat. In the Sprague-Dawley rat, only the posterior frontal Cranial Suture undergoes fusion between 12 and 22 days of age, while all other Cranial Sutures remain patent. Therefore, immunohistochemical analysis of the fusing posterior frontal Suture was compared with the patent sagittal Suture at multiple time points from the fetus through adult. Whereas the intensity of immunostaining was the same in the posterior frontal and sagittal Sutures in the fetal rat, there was increased immunoreactivity for TGF-β isoforms in the actively fusing posterior frontal Suture compared with the patent sagittal Suture starting 2 days after birth and continuing until approximately 20 days. There were intensely immunoreactive osteoblasts present during fusion of the posterior frontal Suture. In contrast, the patent sagittal Suture was only slightly immunoreactive. A differential immunostaining pattern was observed among the TGF-β isoforms; TGF-β2 was the most immunoreactive isoform and was also most strongly associated with osteoblasts adjacent to the dura and the margin of the fusing Suture. Since the increased expression of TGF-β2 during Suture fusion suggested a possible regulatory role, recombinant TGF-β2 was added directly to the posterior frontal and sagittal Sutures in vivo to determine if Suture fusion could be initiated. Exogenously added TGF-β2 stimulated fusion of the ectoCranial surface of the posterior frontal Suture. These data provide evidence for a regulatory role for these growth factors in Cranial Suture development and fusion. Additionally, the intense immunostaining for TGF-β2 in the dura mater underlying the fusing Suture supports a role for the dura mater in Suture fusion. It is possible that premature or excessive expression of these factors may be involved in the etiopathogenesis of craniosynostosis and that modulation of the growth factor profile at the Suture site may have potential therapeutic value.
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studies in Cranial Suture biology iv temporal sequence of posterior frontal Cranial Suture fusion in the mouse
Plastic and Reconstructive Surgery, 1996Co-Authors: James P. Bradley, Jamie P Levine, Joseph G Mccarthy, Douglas A Roth, Michael T. LongakerAbstract:Abstract The biology underlying normal and premature Cranial Suture fusion remains unknown. To develop a model for normal Cranial Suture fusion, the temporal sequence of the posterior frontal Cranial Suture fusion in the mouse was determined. To do this, all the Cranial Sutures of three distinct strains of mice (CD-1, CF-1, and C57bl-6) were studied histologically for fusion at sequential time points. Two studies were set up using group A mice (n = 72, all Sutures studied) and group B mice (n = 78, only the posterior frontal Suture studied, but more precisely along its anatomic length). In the group A Cranial Suture study, mice were sacrificed starting at newborn age and then every 5 days until age 50 days. In addition, two mature mice (250 days old) from each strain were sacrificed. In all three mouse strains, histologic examinations showed that the anterior frontal, sagittal, coronal, lambdoid, and occipitointerparietal Sutures remained patent at up to 50 days of age and were patent in the 250-day mature mice. However, examination of the midpoint of the posterior frontal Suture showed patency at 30 days, partial fusion at 35 days, and complete fusion by 40 days. These data prompted the posterior frontal Suture fusion study. In the group B posterior frontal Suture fusion study, mice were sacrificed at age 23 days and then every 2 days until 47 days of age. The anterior, midpoint, and posterior aspects of the posterior frontal Suture were examined: The anterior aspect fused between 25 and 29 days; the midpoint fused between 31 and 37 days; and the posterior aspect fused between 39 and 45 days. These data indicate that fusion of the posterior frontal Cranial Suture in the mouse proceeds in a defined temporal sequence from an anterior to posterior direction in three distinct strains of mice, while in the same mice all other Cranial Sutures remain patent. By describing and understanding the fusion of the normal posterior frontal Suture, a biologic basis of normal Suture development and fusion can be established and used as a comparison for murine Cranial Sutures altered surgically, biochemically (with growth factors), or genetically (with craniosynostotic phenotypes).