Increased p21 expression in chondrocytes of achondroplasic children independently from the presence of the G380R FGFR3 mutation.
BACKGROUND
Achondroplasia (ACH) represents the major cause of dwarfism and is due to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. The cellular mechanisms involved in the reduced growth have been mainly described for in vitro or in vivo models, but few data have been obtained for humans.


METHODS
Thirteen children with ACH were enrolled in the study; the presence of FGFR3 mutations was determined by restriction fragment length polymorphism analysis and sequencing, whereas protein expression in cartilage biopsy was assessed by immunohistochemistry.


RESULTS
Chondrocytes in cartilage biopsies of ACH children were characterized by the presence of growth arrest mediated by STAT activation (both STAT1 and STAT5) and increased expression of p21 and cyclin D1, whereas no expression of either p53 or cyclin D3 could be detected. This mechanism was present in ACH children carrying the G380R mutation but also in a patient in whom no mutation could be detected in the entire coding region of the FGFR3 gene.


CONCLUSIONS
These data thus demonstrate the presence of a common final mechanism involving p21 and possibly leading to a block in chondrocyte proliferation.
Parafioriti
Antonina
A
Pathology Department, Orthopaedic Institute Gaetano Pini, Milan, Italy.
del Bianco
Silvia
S
Barisani
Donatella
D
Armiraglio
Elisabetta
E
Peretti
Giovanni
G
Albisetti
Walter
W
D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D019902:Chondrocytes / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019938:Cyclin D1; D051498:Receptor, Fibroblast Growth Factor, Type 3