title: Signaling pathways implicated in PGF2alpha effects on Fgf2+/+ and Fgf2-/- osteoblasts.
abstract: Prostaglandin F2alpha (PGF2alpha) regulates fibroblast growth factor-2 (FGF-2) and fibroblast growth factor receptor (FGFR) expression in osteoblasts. Here, the role of FGF-2 in PGF2alpha-induced proliferation and the signaling pathway involved, were determined in calvarial osteoblasts (COBs) from Fgf2+/+ and Fgf2-/- mice. The involvement of the exported FGF-2 isoform, was determined using the FGF-2 neutralizing antibody to alter its binding to FGFR1. PGF2alpha increased activity of Ras, and MAP-kinase cascade as well as Bcl-2 and c-Myc levels in Fgf2+/+ but not in Fgf2-/- COBs. Moreover, in Fgf2+/+ COBs, PGF2alpha-enhanced nuclear accumulation and co-localization of Bcl-2/c-Myc. Although up-regulation of multiple proliferative and survival signals were induced by PGF2alpha in Fgf2+/+ COBs, phospho-p53 was unmodified while p53 was increased. Increased phospho-p53 was, instead, found in Fgf2-/- COBs without up-regulation of oncogenic proteins. The lack of p53 activation in wild type osteoblasts could be due in part to the overexpression of MDM2 caused by PGF2alpha via FGF-2. PGF2alpha, also, increased cyclins D and E in Fgf2+/+ COBs and induced an expansion of Fgf2+/+ osteoblasts in G(2)/M phase. These data clearly show that PGF2alpha induces proliferation via endogenous FGF-2 and the exported isoform mediates PGF2alpha effects by acting in autocrine manner. Furthermore, silencing of FGFR1 in Fgf2+/+ COBs blocked PGF2alpha induced increase of phospho-MDM2 and cyclins.
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Camerino, MC, Italy. giovanna.sabbieti@unicam.it
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Sabbieti
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Agas
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchetti
authors.forename: Giorgio
authors.initials: G
authors.lastname: Santoni
authors.forename: Consuelo
authors.initials: C
authors.lastname: Amantini
authors.forename: Liping
authors.initials: L
authors.lastname: Xiao
authors.forename: Giovanna
authors.initials: G
authors.lastname: Menghi
authors.forename: Marja M
authors.initials: MM
authors.lastname: Hurley
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000172:deficiency* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012886:Skull / Q000166:cytology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D016222:Fibroblast Growth Factor 2; D015237:Dinoprost; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051496:Receptor, Fibroblast Growth Factor, Type 1; D018631:ras Proteins