Parathyroid hormone affects the fibroblast growth factor–proteoglycan signaling axis to regulate osteosarcoma cell migration

Abstract

Parathyroid hormone (PTH)(1-34), which has been established to have a dual effect on bone metabolism, was recently found to regulate osteosarcoma cell migration. A significant part of the bone anabolic action of PTH(1-34) is attributed to fibroblast growth factor (FGF)-2 stimulation. Furthermore, it was recently suggested that the FGF-proteoglycan axis may form an extracellular matrix-related regulatory feedback loop that controls osteoblastic lineage cell proliferation and execution of the osteogenic program. In this study, we investigated the possible participation of FGF-2 signaling in PTH(1-34)-dependent osteosarcoma cell migration. FGF-2 treatment of osteosarcoma cells resulted in a significant increase (P £ 0.01) in MG63 cell migration, similar to that caused by PTH(1-34). mRNA expression analysis of cells treated with PTH(1-34) showed a strong increase in FGF-2 transcript levels (P = 0.0015). Interestingly, the addition of FGF-2 to MG63 cells led to significant downregulation of small leucine-rich proteoglycan biglycan expression at both the mRNA (P £ 0.0001) and protein (60%) levels. In order to examine the significance of biglycan on MG63 cell migration, transfection with short interfering RNA specific for biglycan was performed, resulting in a significant increase (P £ 0.01) in the migration capacity of biglycan-deficient MG63 cells. In contrast, exogenous human recombinant biglycan strongly inhibited the migration of these cells (P £ 0.01). Finally, a direct correlation between PTH(1-34) action and biglycan expression was established by the finding of a significant decrease (P £ 0.01) in biglycan transcript levels in PTH(1-34)-treated cells. To summarize, the present study demonstrates a novel cooperative mechanism of PTH(1-34) and FGF-2 action that results in specific alteration of the biglycan extracellular matrix content to regulate osteosarcoma cell migration.

Receptor Tyrosine Kinases in Osteosarcoma: Not Just the Usual Suspects

“…Oncomine (Compendia Biosciences, Ann Arbor, MI) was also used for the analysis and visualization of osteosarcoma studies showing FGFR2 mRNA overexpression osteosarcoma biopsy samples compared to other sarcomas [ 108 , 109 ]. Furthermore, a previous study demonstrated that FGF2, an FGFR ligand, upregulated migration in an osteosarcoma cell line [ 110 ]. This is consistent with our results indicating that FGFR2 is phosphorylated and promotes the motility and colony formation of the metastatic LM7 cells.…”

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

“…Accordingly, several reports describe biglycan-dependent induction of cell migration in various types of non-carcinoma cells [172, 178, 185]. In contrast, in osteosarcoma cells, biglycan reduces migratory capacity [186]. Interestingly, in lung fibroblasts biglycan activates the signaling pathways of RhoA and Rac1 thereby stimulating migration of these cells [185].…”

The Biology of Small Leucine-rich Proteoglycans in Bone Pathophysiology

“…Dissection of the sets of genes that control the behavior of Bgn-null pre-osteoblasts using oligonucleotide microarrays revealed that Bgn deficiency affects the genes that control inflammation, immune response, and growth of tumor cells (73). Indeed, biglycan affects osteoblastic tumor cell behavior, as it was recently suggested that osteosarcoma cells utilize Runx2 and the FGF-2/syndecan/heparan sulfate proteoglycan axis, a key effector of the osteogenic program, to regulate their migration in a manner dependent on biglycan expression (74). Furthermore, osteosarcoma markers of poor response to therapy (Huvos grade I/II response defines tumors with little or no response to chemotherapy) are predominantly gene products involved in microenvironmental remodeling and osteoclast differentiation, including Bgn (75).…”