title: 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.
authors.affiliation: Department of Histology-Embryology, Medical School, University of Crete, Heraklion, Greece.
authors.forename: Georgios A
authors.initials: GA
authors.lastname: Datsis
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Berdiaki
authors.forename: Dragana
authors.initials: D
authors.lastname: Nikitovic
authors.forename: Maria
authors.initials: M
authors.lastname: Mytilineou
authors.forename: Pavlos
authors.initials: P
authors.lastname: Katonis
authors.forename: Nikos K
authors.initials: NK
authors.lastname: Karamanos
authors.forename: George N
authors.initials: GN
authors.lastname: Tzanakakis
mesh_terms: D000818:Animals; D058578:Biglycan / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058578:Biglycan; D010281:Parathyroid Hormone; D011509:Proteoglycans; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016222:Fibroblast Growth Factor 2