title: Bone sialoprotein mediates human endothelial cell attachment and migration and promotes angiogenesis.
abstract: Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in sites of biomineralization. Recently, we demonstrated that BSP is strongly upregulated in osteotropic cancers and particularly those that exhibit microcalcifications. BSP contains an Arg-Gly-Asp (RGD) motif found in other adhesive molecules that interact with cellular integrins. In bone, BSP has been shown to mediate the attachment of osteoblasts and osteoclasts via alpha(v)beta(3) integrin receptors. Ligands for alpha(v)beta(3) integrin are considered to play a central role during angiogenesis. Therefore, we used human umbilical vein endothelial cells (HUVECs) to study the potential role of BSP in angiogenesis. We found that purified eukaryotic recombinant human BSP (rhBSP) is able to promote both adhesion and chemotactic migration of HUVECs in a dose-dependent manner. These interactions involve HUVEC alpha(v)beta(3) integrin receptors and the RGD domain of BSP. Indeed, HUVECs attach to a recombinant BSP fragment containing the RGD domain, whereas this response is not observed with the same fragment in which RGD has been mutated to Lys-Ala-Glu (KAE). A cyclic RGD BSP peptide inhibits both adhesion and migration of HUVECs to rhBSP. Moreover, anti-alpha(v)beta(3) but not anti-alpha(v)beta(5) monoclonal antibodies also prevent BSP-mediated adhesion and migration of HUVECs. We observed that both rhBSP and the RGD BSP recombinant fragment stimulated ongoing angiogenesis on the chorioallantoic chick membrane assay. BSP angiogenic activity was inhibited by anti-alpha(v)beta(3) antibody, and the KAE BSP fragment was inactive. Our findings represent the first report implicating BSP in angiogenesis. BSP could play a critical role in angiogenesis associated with bone formation and with tumor growth and metastatic dissemination.
authors.affiliation: Metastasis Research Laboratory, University of Liège, Liège, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Bellahcène
authors.forename: K
authors.initials: K
authors.lastname: Bonjean
authors.forename: B
authors.initials: B
authors.lastname: Fohr
authors.forename: N S
authors.initials: NS
authors.lastname: Fedarko
authors.forename: F A
authors.initials: FA
authors.lastname: Robey
authors.forename: M F
authors.initials: MF
authors.lastname: Young
authors.forename: L W
authors.initials: LW
authors.lastname: Fisher
authors.forename: V
authors.initials: V
authors.lastname: Castronovo
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D019030:Receptors, Vitronectin / Q000502:physiology; D012795:Sialoglycoproteins / Q000502:physiology*
chemical_list: C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D019030:Receptors, Vitronectin; D012795:Sialoglycoproteins