title: Sclerostin stimulates angiogenesis in human endothelial cells.
abstract: Sclerostin, negative regulator of bone formation, has been originally known as an osteocyte product. Recently, it has been also detected in hypertrophic chondrocytes, distinctive cells of avascular cartilage which is invaded by capillaries and then replaced by vascularized bone. Thus, we hypothesized that sclerostin, in addition to its role already known, may exert an angiogenic activity. We first proved that sclerostin increased the proliferation of human umbilical vein endothelial cells (HUVECs), and next, by using the chicken chorioallantoic membrane (CAM) in vivo assay, we demonstrated that it exerts an angiogenic activity similar to that of vascular endothelial growth factor (VEGF). This last finding was reinforced by several in vitro approaches. Indeed, we showed that sclerostin induced the formation of a network of anastomosing tubules, a significant increase in the percentage of tubule number, total tubule length and number of junctions, as well as the ability of sclerostin-stimulated HUVECs to organize capillary-like structures and closed-meshes similar to VEGF. The angiogenic response elicited by the protein may be due to the binding to its receptor, LRP6, which is highly expressed at mRNA and protein levels by sclerostin treated HUVECs and through the production of two well-known pro-angiogenic cytokines, VEGF and placental growth factor (PlGF). Finally, we demonstrated that sclerostin was also responsible for the recruitment of osteoclasts and their circulating monocyte progenitors. Overall, these findings showed for the first time the new angiogenic in vitro role of sclerostin which could be also considered as a novel molecule in angiogenesis-osteogenesis coupling.
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Oranger
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Giacomina
authors.initials: G
authors.lastname: Brunetti
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Graziana
authors.initials: G
authors.lastname: Colaianni
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tamma
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carbone
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Lippo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mori
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pignataro
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Cirulli
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zerlotin
authors.affiliation: Orthopaedics Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, Faculty of Medicine and Surgery, University of Bari, General Hospital, Bari, Italy.
authors.forename: Biagio
authors.initials: B
authors.lastname: Moretti
authors.affiliation: Orthopaedics Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, Faculty of Medicine and Surgery, University of Bari, General Hospital, Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Notarnicola
authors.affiliation: National Cancer Institute "Giovanni Paolo II", Bari, Italy; Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Department of Emergency and Organ Transplantation, University of Bari Medical School, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grano
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, Section of Human Anatomy and Histology, University of Bari, Bari, Italy. Electronic address: silviaconcetta.colucci@uniba.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Colucci
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D049033:Chorioallantoic Membrane / Q000166:cytology / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D005819:Genetic Markers; C422903:SOST protein, human
keywords: Angiogenesis; Bone formation; Endothelial cells; Sclerostin