Abstract
Apert syndrome, associated with fibroblast growth factor receptor (FGFR) 2
mutations, is characterized by premature fusion of cranial sutures. We analyzed
proliferation and differentiation of calvaria cells derived from Apert infants
and fetuses with FGFR-2 mutations. Histological analysis revealed premature
ossification, increased extent of subperiosteal bone formation, and alkaline
phosphatase- positive preosteoblastic cells in Apert fetal calvaria compared
with age-matched controls. Preosteoblastic calvaria cells isolated from Apert
infants and fetuses showed normal cell growth in basal conditions or in response
to exogenous FGF-2. In contrast, the number of alkaline phosphatase- positive
calvaria cells was fourfold higher than normal in mutant fetal calvaria cells
with the most frequent Apert FGFR-2 mutation (Ser252Trp), suggesting increased
maturation rate of cells in the osteoblastic lineage. Biochemical and Northern
blot analyses also showed that the expression of alkaline phosphatase and type 1
collagen were 2-10-fold greater than normal in mutant fetal calvaria cells. The
in vitro production of mineralized matrix formed by immortalized mutant fetal
calvaria cells cultured in aggregates was also increased markedly compared with
control immortalized fetal calvaria cells. The results show that Apert FGFR-2
mutations lead to an increase in the number of precursor cells that enter the
osteogenic pathway, leading ultimately to increased subperiosteal bone matrix
formation and premature calvaria ossification during fetal development, which
establishes a connection between the altered genotype and cellular phenotype in
Apert syndromic craniosynostosis.
Authors
A Lomri, J Lemonnier, M Hott, N de Parseval, E Lajeunie, A Munnich, D Renier, P J Marie
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