Heparan sulphate sugar chain are involved in PGF2alpha-induced osteoblast growth and differentiation

Heparan sulfate proteoglycans (HSPGs) consist of a protein core and heparan sulfate (HS) glycosaminoglycan chains which confer structural and functional diversity (1). HSPGs are required for fibroblast growth factor (FGF) binding to its tyrosine kinase receptor. They are also considered dynamic regulators of FGF signaling (2). The role of PGF2alpha as modulator of HSPGs, FGF-2 and FGF receptors (FGFRs) was evaluated in order to better understand PGF2alpha-mediated signalling in osteoblast metabolism. The novel observation that PGF2alpha was able to promote the formation of HSPGs/FGF-2/FGFRs complexes is hereby depicted. Our data also suggested that PGF2alpha could induce new synthesis of HS chains on osteoblasts by a mechanism involving a modulation of MAPK signaling and that HS is required for the regulation of FGF-2 induced by PGF2. In particular, we showed that HSPGs are necessary for the expression of phospho-p44/42, since their proteolytic cleavage before PGF2alpha administration down-regulated phospho-p44/42 basal expression, likely inhibiting FGFRs tyrosine kinase activity. Interestingly, MAPK signalling influenced syntheses and localization of FGF-2, its specific receptor and HS. In addition, HSPGs proteolytic cleavage and MAPK kinase inhibition also revealed that PGFalpha-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 PGF2alpha modulates Runx2 expression by FGFR1 and HS.