Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones
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Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones. / Maes, Christa; Goossens, Steven; Bartunkova, Sonia; Drogat, Benjamin; Coenegrachts, Lieve; Stockmans, Ingrid; Moermans, Karen; Nyabi, Omar; Haigh, Katharina; Naessens, Michael; Haenebalcke, Lieven; Tuckermann, Jan P; Tjwa, Marc; Carmeliet, Peter; Mandic, Vice; David, Jean-Pierre; Behrens, Axel; Nagy, Andras; Carmeliet, Geert; Haigh, Jody J.
in: EMBO J, Jahrgang 29, Nr. 2, 20.01.2010, S. 424-41.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Increased skeletal VEGF enhances beta-catenin activity and results in excessively ossified bones
AU - Maes, Christa
AU - Goossens, Steven
AU - Bartunkova, Sonia
AU - Drogat, Benjamin
AU - Coenegrachts, Lieve
AU - Stockmans, Ingrid
AU - Moermans, Karen
AU - Nyabi, Omar
AU - Haigh, Katharina
AU - Naessens, Michael
AU - Haenebalcke, Lieven
AU - Tuckermann, Jan P
AU - Tjwa, Marc
AU - Carmeliet, Peter
AU - Mandic, Vice
AU - David, Jean-Pierre
AU - Behrens, Axel
AU - Nagy, Andras
AU - Carmeliet, Geert
AU - Haigh, Jody J
PY - 2010/1/20
Y1 - 2010/1/20
N2 - Vascular endothelial growth factor (VEGF) and beta-catenin both act broadly in embryogenesis and adulthood, including in the skeletal and vascular systems. Increased or deregulated activity of these molecules has been linked to cancer and bone-related pathologies. By using novel mouse models to locally increase VEGF levels in the skeleton, we found that embryonic VEGF over-expression in osteo-chondroprogenitors and their progeny largely pheno-copied constitutive beta-catenin activation. Adult induction of VEGF in these cell populations dramatically increased bone mass, associated with aberrant vascularization, bone marrow fibrosis and haematological anomalies. Genetic and pharmacological interventions showed that VEGF increased bone mass through a VEGF receptor 2- and phosphatidyl inositol 3-kinase-mediated pathway inducing beta-catenin transcriptional activity in endothelial and osteoblastic cells, likely through modulation of glycogen synthase kinase 3-beta phosphorylation. These insights into the actions of VEGF in the bone and marrow environment underscore its power as pleiotropic bone anabolic agent but also warn for caution in its therapeutic use. Moreover, the finding that VEGF can modulate beta-catenin activity may have widespread physiological and clinical ramifications.
AB - Vascular endothelial growth factor (VEGF) and beta-catenin both act broadly in embryogenesis and adulthood, including in the skeletal and vascular systems. Increased or deregulated activity of these molecules has been linked to cancer and bone-related pathologies. By using novel mouse models to locally increase VEGF levels in the skeleton, we found that embryonic VEGF over-expression in osteo-chondroprogenitors and their progeny largely pheno-copied constitutive beta-catenin activation. Adult induction of VEGF in these cell populations dramatically increased bone mass, associated with aberrant vascularization, bone marrow fibrosis and haematological anomalies. Genetic and pharmacological interventions showed that VEGF increased bone mass through a VEGF receptor 2- and phosphatidyl inositol 3-kinase-mediated pathway inducing beta-catenin transcriptional activity in endothelial and osteoblastic cells, likely through modulation of glycogen synthase kinase 3-beta phosphorylation. These insights into the actions of VEGF in the bone and marrow environment underscore its power as pleiotropic bone anabolic agent but also warn for caution in its therapeutic use. Moreover, the finding that VEGF can modulate beta-catenin activity may have widespread physiological and clinical ramifications.
KW - Animals
KW - Bone and Bones
KW - Cell Differentiation
KW - Cell Proliferation
KW - Cells, Cultured
KW - Endothelial Cells
KW - Gene Expression Regulation, Developmental
KW - Humans
KW - Mesoderm
KW - Mice
KW - Mice, Transgenic
KW - Morphogenesis
KW - Osteoblasts
KW - Phosphatidylinositol 3-Kinases
KW - Stem Cells
KW - Stromal Cells
KW - Vascular Endothelial Growth Factor A
KW - beta Catenin
U2 - 10.1038/emboj.2009.361
DO - 10.1038/emboj.2009.361
M3 - SCORING: Journal article
C2 - 20010698
VL - 29
SP - 424
EP - 441
JO - EMBO J
JF - EMBO J
SN - 0261-4189
IS - 2
ER -