Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model

Shen, Kangping; Krakora, SM; Cunningham, Michael L.; Singh, Mohini; Wang, X; Hu, F. Z.; Jc, Post; Ehrlich, Garth D.

doi:10.1111/j.1601-6343.2009.01460.x

Cited by 27 publications

(23 citation statements)

References 21 publications

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“…Since Noggin expression in sutures is downregulated by FGF signaling, these findings suggest a possibility for the therapeutic use of Noggin to treat craniosynostosis caused by hyperactivation of FGF signaling [64]. Indeed, Noggin can suppress suture fusions experimentally induced by transplantation of osteoblasts expressing a mutant form of FGFR2 [65]. Noggin treatment also inhibits recurrence of suture fusion subsequent to suturectomy in a rabbit model of bilateral coronal synostosis [66].…”

Section: Bmp Signalingmentioning

confidence: 99%

Neural crest cell signaling pathways critical to cranial bone development and pathology

Mishina

Snider

2014

Experimental Cell Research

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Neural crest cells appear early during embryogenesis and give rise to many structures in the mature adult. In particular, a specific population of neural crest cells migrates to and populates developing cranial tissues. The ensuing differentiation of these cells via individually complex and often intersecting signaling pathways is indispensible to growth and development of the craniofacial complex. Much research has been devoted to this area of development with particular emphasis on cell signaling events required for physiologic development. Understanding such mechanisms will allow researchers to investigate ways in which they can be exploited in order to treat a multitude of diseases affecting the craniofacial complex. Knowing how these multipotent cells are driven towards distinct fates could, in due course, allow patients to receive regenerative therapies for tissues lost to a variety of pathologies. In order to realize this goal, nucleotide sequencing advances allowing snapshots of entire genomes and exomes are being utilized to identify molecular entities associated with disease states. Once identified, these entities can be validated for biological significance with other methods. A crucial next step is the integration of knowledge gleaned from observations in disease states with normal physiology to generate an explanatory model for craniofacial development. This review seeks to provide a current view of the landscape on cell signaling and fate determination of the neural crest and to provide possible avenues of approach for future research.

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Section: Bmp Signalingmentioning

confidence: 99%

Neural crest cell signaling pathways critical to cranial bone development and pathology

Mishina

Snider

2014

Experimental Cell Research

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“…Thus, the authors of this study concluded that overactive FGF/FGFR signaling (as seen in FGFR2 gain-of-function mutations) decreased sutural expression of the BMP antagonist Noggin, leading to increased suture osteogenesis and eventually suture fusion [Warren et al, 2003]. Subsequently, Shen et al [2009] could demonstrate in their chimeric rat model that coronal sutures remained patent when xenotransplantation with mutant FGFR2 osteoblasts was performed together with co-application of recombinant human Noggin. To test the long-term effects of Noggin exposure on suture patency in a murine model, a gel-foam scaffold loaded with Noggin and GFP-expressing cells was placed onto the suturectomy sites.…”

Section: Tgfß/bmp Signalingmentioning

confidence: 94%

Current Approaches in the Development of Molecular and Pharmacological Therapies in Craniosynostosis Utilizing Animal Models

Rachwalski¹,

Khonsari

Paternoster³

2018

Mol Syndromol

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The development of the craniofacial skeleton is a spatial and temporal process where cranial sutures play a role in the regulation of morphogenesis and growth. Disruption of these cellular and molecular interactions may lead to craniosynostosis, the premature obliteration of one or more cranial sutures, yielding skull growth restriction and malformation perpendicular to the affected suture. Facial deformity and various functional CNS anomalies are other frequent complications. Cranial vault expansion and reconstructive surgery remain the mainstay of treatment but pose an elevated risk of morbidity for the infant. While the etiology of nonsyndromic craniosynostosis remains to be deciphered, gain-of-function mutations in FGFR1-3 and TWIST1 were found to be responsible for more than 3/4 of the most commonly encountered craniofacial syndromes. Animal models have been invaluable to further dissect the role of genes within the cranial sutures and for the development of alternative nonsurgical treatment strategies. In this review, we will present various molecular and pharmacological approaches for the treatment of craniosynostosis that have been tested using in vitro and in vivo assays as well as discuss their potential application in humans focusing on the case of tyrosine kinase inhibitors.

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“…Although progress has been made to elucidate the events surrounding the cranial suture's fate, predominantly on the molecular and genetic basis, the cause of premature fusion is unknown and much of the suture biology remains poorly understood (David et al, 1982;Kokich, 1986;Slater et al, 2009). In this context, data on bone structure and composition alongside the bony edges of sutures is extremely scarce or contradictory (Enlow, 1982;David et al, 1982;Kokich, 1986;De Pollack et al, 1996;Sherick et al, 2000;Vastardis et al, 2004;Regelsberger et al, 2009). Moreover, it is unknown whether the ossification process in craniosynostosis is pathological itself, or whether it just commences too early.…”

Section: Introductionmentioning

confidence: 99%

“…In suture fusion, type 1 collagen, TGF-beta, FGFR and SPP-1 have been identified to be upregulated in the suture matrix, whereas CBFA1, FGF-2 and IGF-1 become expressed in the adjacent bone borders (Hunenko et al, 2001;Chong et al, 2003;Ignelzi et al, 2003;Eswarakumar et al, 2004;Tholpady et al, 2004;Mooney et al, 2007;Coussens et al, 2008;Moenning et al, 2009;Shen et al, 2009). These processes are most likely occurring in response to external stimuli like the expanding brain (Kokich, 1986;Davis et al, 2009;Oppenheimer et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…These processes are most likely occurring in response to external stimuli like the expanding brain (Kokich, 1986;Davis et al, 2009;Oppenheimer et al, 2009). The internal periosteum under the dura mater and the external periosteum may influence bone formation and suture fusion, but the amount and nature of their influences as well as the exact signalling pathway in normal and pathological suture fusion are still unknown (Mooney et al, 2001;Shen et al, 2009;Slater et al, 2009;Wilczak and Ousley, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development

Regelsberger¹,

Milovanović²,

Schmidt³

et al. 2012

eCM

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Premature fusion of cranial sutures is a common problem with an incidence of 3-5 per 10,000 live births. Despite progress in understanding molecular/genetic factors affecting suture function, the complex process of premature fusion is still poorly understood. In the present study, corresponding excised segments of nine patent and nine prematurely fused sagittal sutures from infants (age range 3-7 months) with a special emphasis on their hierarchical structural configuration were compared. Cell, tissue and architecture characteristics were analysed by transmitted and polarised light microscopy, 2D-histomorphometry, backscattered electron microscopy and energy-dispersivex-ray analyses. Apart from wider sutural gaps, patent sutures showed histologically increased new bone formation compared to reduced new bone formation and osseous edges with a more mature structure in the fused portions of the sutures. This pattern was accompanied by a lower osteocyte lacunar density and a higher number of evenly mineralised osteons, reflecting pronounced lamellar bone characteristics along the prematurely fused sutures. In contrast, increases in osteocyte lacunar number and size accompanied by mineralisation heterogeneity and randomly oriented collagen fibres predominantly signified woven bone characteristics in patent, still growing suture segments. The already established woven-to-lamellar bone transition provides evidence of advanced bone development in synostotic sutures. Since structural and compositional features of prematurely fused sutures did not show signs of pathological/defective ossification processes, this supports the theory of a normal ossification process in suture synostosis -just locally commencing too early. These histomorphological findings may provide the basis for a better understanding of the pathomechanism of craniosynostosis, and for future strategies to predict suture fusion and to determine surgical intervention.

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Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model

Cited by 27 publications

References 21 publications

Neural crest cell signaling pathways critical to cranial bone development and pathology

Neural crest cell signaling pathways critical to cranial bone development and pathology

Current Approaches in the Development of Molecular and Pharmacological Therapies in Craniosynostosis Utilizing Animal Models

Changes to the cell, tissue and architecture levels in cranial suture synostosis reveal a problem of timing in bone development

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