The present investigation extends our previous studies on PGF2α-mediated signalling in osteoblast metabolism. In particular, the role of PGF2α as modulator of heparan sulphate proteoglycans (HSPGs), fibroblast growth factor 2 (FGF-2) and fibroblast growth factor receptors (FGFRs) was evaluated. We hereby reported the novel observation that PGF2α was able to promote the formation of HSPGs/FGF-2/FGFRs complexes. Moreover, our data suggested that PGF2α could induce new synthesis of heparan sulphate (HS) chains on osteoblasts by a mechanism involving a modulation of MAPK signalling and that HS is required for the regulation of FGF-2 induced by PGF2α. Indeed, a proteolytic cleavage of HSPGs with heparinase III (Hep III) prior to PGF2α administration down-regulated the basal expression of phospho-p44/42, likely inhibiting FGFRs tyrosine kinase activity. Interestingly, MAPK signalling influenced syntheses and subcellular localization of FGF-2, its specific receptor and HS. In addition, the proteolytic cleavage by Hep III and the MAPK kinase inhibition by PD-98059 also revealed that PGF2α induced cell proliferation is dependent on HSPGs and FGF-2 specific receptor, respectively. Of further relevance of this study, we demonstrated, by using a specific siRNA for FGFR1, that PGF2α modulates Runx2 expression by FGFR1 and HS.

Prostaglandin F2alpha involves heparan sulfate sugar chains and FGFRs to modulate osteoblast growth and differentiation

SABBIETI, Maria Giovanna;AGAS, DIMITRIOS;MARCHETTI, Luigi
2008

Abstract

The present investigation extends our previous studies on PGF2α-mediated signalling in osteoblast metabolism. In particular, the role of PGF2α as modulator of heparan sulphate proteoglycans (HSPGs), fibroblast growth factor 2 (FGF-2) and fibroblast growth factor receptors (FGFRs) was evaluated. We hereby reported the novel observation that PGF2α was able to promote the formation of HSPGs/FGF-2/FGFRs complexes. Moreover, our data suggested that PGF2α could induce new synthesis of heparan sulphate (HS) chains on osteoblasts by a mechanism involving a modulation of MAPK signalling and that HS is required for the regulation of FGF-2 induced by PGF2α. Indeed, a proteolytic cleavage of HSPGs with heparinase III (Hep III) prior to PGF2α administration down-regulated the basal expression of phospho-p44/42, likely inhibiting FGFRs tyrosine kinase activity. Interestingly, MAPK signalling influenced syntheses and subcellular localization of FGF-2, its specific receptor and HS. In addition, the proteolytic cleavage by Hep III and the MAPK kinase inhibition by PD-98059 also revealed that PGF2α induced cell proliferation is dependent on HSPGs and FGF-2 specific receptor, respectively. Of further relevance of this study, we demonstrated, by using a specific siRNA for FGFR1, that PGF2α modulates Runx2 expression by FGFR1 and HS.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/201286
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