title: P253R fibroblast growth factor receptor-2 mutation induces RUNX2 transcript variants and calvarial osteoblast differentiation.
abstract: Unregulated fibroblast growth factor 2 (FGF2) signaling caused by mutations in the fibroblast growth factor receptor (FGFR2) leads to human craniosynostosis such as the Apert syndrome. In an in vitro control model of calvarial osteoblasts from Apert patients carrying the FGFR2 P253R mutation, we studied the changes in cellular phenotype and evaluated the effects of FGF2. Compared with wild-type controls, osteocalcin mRNA was down-regulated in Apert osteoblasts, Runt-related transcription factor-2 (RUNX2) mRNA was differentially spliced, and FGF2 secretion was greater. Total protein synthesis, fibronectin and type I collagen secretion were up-regulated, while protease and glycosidase activities and matrix metalloproteinase-13 (MMP-13) transcription were decreased, suggesting an altered ECM turnover. Adding FGF2 increased protease and glycosidase activities and down-regulated fibronectin and type I collagen secretion in Apert osteoblasts. High affinity FGF2 receptors were up-regulated in Apert osteoblasts and analysis of signal transduction showed elevated levels of Grb2 tyrosine phosphorylation and the Grb2-p85 beta association, which FGF2 stimulation strongly reduced. All together these findings suggest increased constitutive receptor activity in Apert mutant osteoblasts and an autocrine loop involving the FGF2 pathway in modulation of Apert osteoblast behavior.
authors.affiliation: Institute of Histology and General Embryology, University of Perugia, Perugia, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Baroni
authors.forename: Paolo
authors.initials: P
authors.lastname: Carinci
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lilli
authors.forename: Catia
authors.initials: C
authors.lastname: Bellucci
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Aisa
authors.forename: Luca
authors.initials: L
authors.lastname: Scapoli
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Francesco
authors.initials: F
authors.lastname: Carinci
authors.forename: Furio
authors.initials: F
authors.lastname: Pezzetti
authors.forename: Mario
authors.initials: M
authors.lastname: Calvitti
authors.forename: Antonio
authors.initials: A
authors.lastname: Farina
authors.forename: Carmela
authors.initials: C
authors.lastname: Conte
authors.forename: Maria
authors.initials: M
authors.lastname: Bodo
mesh_terms: D000168:Acrocephalosyndactylia / Q000235:genetics* / Q000473:pathology*; D000293:Adolescent; D001120:Arginine; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010006:Osteoblasts / Q000473:pathology*; D010294:Parietal Bone; D011392:Proline; D012333:RNA, Messenger / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; D001120:Arginine; D011392:Proline; C496353:FGFR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2