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 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.
Highlights
Skull growth occurs via intramembranous bone deposition along the outer edge of each cranial vault bone, in coordination with endochondral growth of cranial base bones at the cranial base synchondroses
The FGFR2C342Y/+ mutation was previously demonstrated to cause ligand independent signaling and is widely considered to be an activating mutation leading to increased FGF signaling [18,19,20,21]. We pursued this investigation because we previously demonstrated that FGF signaling diminishes tissue nonspecific alkaline phosphatase (TNAP) expression [22,23,24], and showed that TNAP deficiency in mice leads to a similar craniofacial phenotype to that seen in FGFR2C342Y/+ Crouzon mice including coronal but not sagittal craniosynostosis, deficient growth of the cranial base with fusion of cranial base synchondroses, and brachycephalic/acrocephalic head shapes [11, 17, 25, 26]
BALB/c FGFR2C342Y/+ mice injected with the lentivirus increased serum AP levels by 1.2 U/mL when compared to BALB/c vehicle treated FGFR2C342Y/+ mice (p
Summary
Skull growth occurs via intramembranous bone deposition along the outer edge of each cranial vault bone, in coordination with endochondral growth of cranial base bones at the cranial base synchondroses (cartilaginous growth plates). Anterior-posterior growth of the skull is dependent upon both cranial vault and cranial base bone growth. Craniosynostosis (which, when syndromic often includes premature fusion of cranial base bones) can lead to high. TNAP rescues craniosynostosis in FGFR2C342Y/+ Crouzon mice
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