title: NPNT is Expressed by Osteoblasts and Mediates Angiogenesis via the Activation of Extracellular Signal-regulated Kinase.
abstract: Angiogenesis plays an important role in bone development and remodeling and is mediated by a plethora of potential angiogenic factors. However, data regarding specific angiogenic factors that are secreted within the bone microenvironment to regulate osteoporosis is lacking. Here, we report that Nephronectin (NPNT), a member of the epidermal growth factor (EGF) repeat superfamily proteins and a homologue of EGFL6, is expressed in osteoblasts. Intriguingly, the gene expression of NPNT is reduced in the bone of C57BL/6J ovariectomised mice and in osteoporosis patients. In addition, the protein levels of NPNT and CD31 are also found to be reduced in the tibias of OVX mice. Exogenous addition of mouse recombinant NPNT on endothelial cells stimulates migration and tube-like structure formation in vitro. Furthermore, NPNT promotes angiogenesis in an ex vivo fetal mouse metatarsal angiogenesis assay. We show that NPNT stimulates the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated kinase (MAPK) in endothelial cells. Inhibition of ERK1/2 impaired NPNT-induced endothelial cell migration, tube-like structure formation and angiogenesis. Taken together, these results demonstrate that NPNT is a paracrine angiogenic factor and may play a role in pathological osteoporosis. This may lead to new targets for treatment of bone diseases and injuries.
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.
authors: Vincent
authors: V
authors: Kuek
authors: Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, China.
authors: Zhifan
authors: Z
authors: Yang
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.
authors: Shek Man
authors: SM
authors: Chim
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.|Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors: Sipin
authors: S
authors: Zhu
authors: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors: Huazi
authors: H
authors: Xu
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.
authors: Siu To
authors: ST
authors: Chow
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.
authors: Jennifer
authors: J
authors: Tickner
authors: Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
authors: Vicki
authors: V
authors: Rosen
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.
authors: Wendy
authors: W
authors: Erber
authors: Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, China.
authors: Xiucheng
authors: X
authors: Li
authors: Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: An
authors: A
authors: Qin
authors: Department of Orthopaedics, Shaoxing People's Hospital, Shaoxing, Zhejiang 312000, China.
authors: Yu
authors: Y
authors: Qian
authors: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands WA 6009, Australia.|Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors: Jiake
authors: J
authors: Xu
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000235:genetics; D010052:Ovariectomy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002070:Butadienes; D016326:Extracellular Matrix Proteins; D009570:Nitriles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C113580:U 0126; C432915:nephronectin