title: EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades.
abstract: Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone.
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Shek Man
authors.initials: SM
authors.lastname: Chim
authors.forename: Vincent
authors.initials: V
authors.lastname: Kuek
authors.forename: Siu To
authors.initials: ST
authors.lastname: Chow
authors.forename: Bay Sie
authors.initials: BS
authors.lastname: Lim
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tickner
authors.forename: Jinmin
authors.initials: J
authors.lastname: Zhao
authors.forename: Rosa
authors.initials: R
authors.lastname: Chung
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Su
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Wendy
authors.initials: W
authors.lastname: Erber
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
authors.forename: Vicki
authors.initials: V
authors.lastname: Rosen
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000098:blood supply / Q000166:cytology; D002135:Calcium-Binding Proteins; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D066255:EGF Family of Proteins; D042783:Endothelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D017102:Fracture Healing / Q000502:physiology; D006132:Growth Plate / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000096:biosynthesis; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000072042:Salter-Harris Fractures; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C479627:Egfl7 protein, mouse; D016023:Integrins; D011506:Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D015675:Osteocalcin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases