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Increased skeletal VEGF enhances β‐catenin activity and results in excessively ossified bones
Author(s) -
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 JeanPierre,
Behrens Axel,
Nagy Andras,
Carmeliet Geert,
Haigh Jody J
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.361
Subject(s) - biology , vascular endothelial growth factor , endocrinology , gsk 3 , medicine , beta catenin , bone marrow , angiogenesis , gsk3b , anabolism , cancer research , microbiology and biotechnology , signal transduction , wnt signaling pathway , immunology , vegf receptors
Vascular endothelial growth factor (VEGF) and β‐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 β‐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 β‐catenin transcriptional activity in endothelial and osteoblastic cells, likely through modulation of glycogen synthase kinase 3‐β 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 β‐catenin activity may have widespread physiological and clinical ramifications.