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From INSERM U 349 Affiliated CNRS, Lariboisière Hospital, Paris, France
Apert syndrome is an autosomal dominant disorder characterized by
premature cranial ossification resulting from fibroblast growth factor
receptor-2 (FGFR-2)-activating mutations. We have studied the effects
of the prominent S252W FGFR-2 Apert mutation on apoptosis and the
underlying mechanisms in human mutant osteoblasts. In
vivo analysis of terminal deoxynucleotidyl transferase-mediated
nick-end labeling revealed premature apoptosis of mature osteoblasts
and osteocytes in the Apert suture compared to normal coronal suture.
In vitro, mutant osteoblasts showed increased
apoptosis, as demonstrated by terminal deoxynucleotidyl
transferase-mediated nick-end labeling analysis, trypan blue
staining, and DNA fragmentation. Mutant osteoblasts also showed
increased activity of caspase-8 and effector caspases (-3,
-6, -7) constitutively. This was related to protein kinase C
activation because the selective protein kinase C inhibitor calphostin
C inhibited caspase-8, effector caspases, and apoptosis
in mutant osteoblasts. Apert osteoblasts also showed increased
expression of interleukin (IL)-1
, IL-1ß,
Fas, and Bax, and decreased Bcl-2 levels. Specific
neutralizing anti-IL-1 antibody reduced Fas levels, Bax
expression, effector caspases activity, and apoptosis
in mutant cells. Thus, the Apert S252W FGFR-2 mutation promotes
apoptosis in human osteoblasts through activation of protein kinase
C, overexpression of IL-1 and Fas, activation of
caspase-8, and increased Bax/Bcl-2 levels, leading to
increased effector caspases and DNA fragmentation. This identifies a
complex FGFR-2 signaling pathway involved in the premature apoptosis
induced by the Apert S252W FGFR-2 mutation in human calvaria
osteoblasts.
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