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.