Apert (Ap) syndrome is characterized by premature cranial suture ossification 
caused by fibroblast growth factor receptor 2 (FGFR-2) mutations. We studied the 
role of cadherins and signaling events in the phenotypic alterations induced by 
the Ap FGFR-2 S252W mutation in mutant immortalized fetal human calvaria 
osteoblasts. The FGFR-2 mutation caused increased expression of the osteoblast 
markers alkaline phosphatase (ALP), type 1 collagen (COLIA1), and osteocalcin 
(OC) in long-term culture. The mutation also increased cell-cell aggregation, 
which was suppressed by specific neutralizing anti-N- and anti-E-cadherin 
antibodies. Mutant osteoblasts showed increased N- and E-cadherin, but not 
N-cell adhesion molecule (N-CAM) messenger RNA (mRNA) and protein levels. This 
was confirmed in vivo by the abundant immunoreactive N- and E-cadherins in 
preosteoblasts in the Ap suture whereas N-CAM and alpha- and beta-catenins were 
unaffected. Neutralizing anti-N-cadherin antibody or N-cadherin antisense (AS) 
oligonucleotides but not anti-E-cadherin antibody or AS reduced ALP activity as 
well as ALP, COLIA1, and OC mRNA overexpression in mutant osteoblasts. Analysis 
of signal transduction revealed increased phospholipase Cgamma (PLCgamma) and 
protein kinase Calpha (PKCalpha) phosphorylation and increased PKC activity in 
mutant cells in basal conditions. Inhibition of PKC by calphostin C or the 
PKCalpha-specific inhibitor Gö6976 suppressed the increased N-cadherin mRNA and 
protein levels as well as the overexpression of ALP, COLIA1, and OC mRNA in 
mutant cells. Thus, N-cadherin plays a role in the activation of osteoblast 
differentiation marker genes in mutant osteoblasts and PKCalpha signaling 
appears to be involved in the increased N-cadherin and osteoblast gene 
expression induced by the S252W FGFR-2 mutation in human osteoblasts.