title: Medical treatment of craniosynostosis: recombinant Noggin inhibits coronal suture closure in the rat craniosynostosis model.
abstract: INTRODUCTION - The mechanisms underlying craniosynostosis remains unknown. However, mutations in FGFR2 are associated with craniosynostotic syndromes. We previously compared gene expression patterns of patent and synostosing coronal sutures in the nude rat and demonstrated down regulation of Noggin in synostosing sutures. Noggin expression is also suppressed by FGF2 and constitutive FGFR2 signaling [Warren et al. (2003) Nature, vol. 422, pp. 625-9; McMahon et al. (1998) Genes Dev, vol. 12, pp. 1438-52]. Thus, we therefore hypothesized that the addition of rhNoggin to prematurely fusing sutures should prevent synostosis. MATERIALS AND METHODS - Cohorts of nude rats were subjected to: 1) surgical elevation of the coronal suture (shams); 2) surgical elevation and placement of normal or FGFR2 mutant human osteoblasts onto the underlying dura (xenotransplants); or 3) xenotransplantation with co-application of heparin acrylic beads soaked with recombinant human (rh) Noggin. Eleven days post-surgery the sutures were harvested, stained, and histologically examined. RESULTS - Animals that received control osteoblasts, sham surgery, or no surgery demonstrated normal skull growth and coronal suture histology, whereas animals transplanted only with FGFR2 mutant osteoblasts showed evidence of bridging synostosis on the calvarial dural surface. Sutures treated with FGFR2 mutant osteoblasts and rhNoggin remained patent. CONCLUSION - The chimeric nude rate model is a viable model of craniosynostosis. FGFR2 mutations in osteoblasts induce bridging osteosynthesis demonstrating one of the mechanisms for premature suture fusion. Topical application of rhNoggin protein prevents craniosynostosis in the weanling nude rat xenotransplantation model of syndromic craniosynostosis.
authors.affiliation: Center for Genomic Sciences, Allegheny Singer Research Institute, Pittsburgh, PA 15212, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shen
authors.forename: S M
authors.initials: SM
authors.lastname: Krakora
authors.forename: M
authors.initials: M
authors.lastname: Cunningham
authors.forename: M
authors.initials: M
authors.lastname: Singh
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: F Z
authors.initials: FZ
authors.lastname: Hu
authors.forename: J C
authors.initials: JC
authors.lastname: Post
authors.forename: G D
authors.initials: GD
authors.lastname: Ehrlich
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics / Q000473:pathology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D002352:Carrier Proteins / Q000627:therapeutic use*; D002460:Cell Line; D019070:Cell Lineage; D002678:Chimera; D003393:Cranial Sutures / Q000473:pathology / Q000601:surgery; D003394:Craniofacial Dysostosis / Q000235:genetics / Q000473:pathology; D003398:Craniosynostoses / Q000517:prevention & control*; D047168:Cystine Knot Motifs; D004195:Disease Models, Animal; D004388:Dura Mater / Q000601:surgery; D005624:Frontal Bone / Q000473:pathology / Q000601:surgery; D006801:Humans; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000637:transplantation; D010294:Parietal Bone / Q000473:pathology / Q000601:surgery; D051381:Rats; D011923:Rats, Nude; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D011994:Recombinant Proteins; D012886:Skull / Q000254:growth & development; D014183:Transplantation, Heterologous; D000099176:Noggin Protein
chemical_list: D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011994:Recombinant Proteins; D000099176:Noggin Protein; C496353:FGFR2 protein, human