title: Neurotrophin-3 Induces BMP-2 and VEGF Activities and Promotes the Bony Repair of Injured Growth Plate Cartilage and Bone in Rats.
abstract: Injured growth plate is often repaired by bony tissue causing bone growth defects, for which the mechanisms remain unclear. Because neurotrophins have been implicated in bone fracture repair, here we investigated their potential roles in growth plate bony repair in rats. After a drill-hole injury was made in the tibial growth plate and bone, increased injury site mRNA expression was observed for neurotrophins NGF, BDNF, NT-3, and NT-4 and their Trk receptors. NT-3 and its receptor TrkC showed the highest induction. NT-3 was localized to repairing cells, whereas TrkC was observed in stromal cells, osteoblasts, and blood vessel cells at the injury site. Moreover, systemic NT-3 immunoneutralization reduced bone volume at injury sites and also reduced vascularization at the injured growth plate, whereas recombinant NT-3 treatment promoted bony repair with elevated levels of mRNA for osteogenic markers and bone morphogenetic protein (BMP-2) and increased vascularization and mRNA for vascular endothelial growth factor (VEGF) and endothelial cell marker CD31 at the injured growth plate. When examined in vitro, NT-3 promoted osteogenesis in rat bone marrow stromal cells, induced Erk1/2 and Akt phosphorylation, and enhanced expression of BMPs (particularly BMP-2) and VEGF in the mineralizing cells. It also induced CD31 and VEGF mRNA in rat primary endothelial cell culture. BMP activity appears critical for NT-3 osteogenic effect in vitro because it can be almost completely abrogated by co-addition of the BMP inhibitor noggin. Consistent with its angiogenic effect in vivo, NT-3 promoted angiogenesis in metatarsal bone explants, an effect abolished by co-treatment with anti-VEGF. This study suggests that NT-3 may be an osteogenic and angiogenic factor upstream of BMP-2 and VEGF in bony repair, and further studies are required to investigate whether NT-3 may be a potential target for preventing growth plate faulty bony repair or for promoting bone fracture healing. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Su
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Rosa
authors.initials: R
authors.lastname: Chung
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Chun-Sheng
authors.initials: CS
authors.lastname: Ruan
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia.
authors.forename: Shek Man
authors.initials: SM
authors.lastname: Chim
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia.
authors.forename: Vincent
authors.initials: V
authors.lastname: Kuek
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Prem P
authors.initials: PP
authors.lastname: Dwivedi
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Mohammadhossein
authors.initials: M
authors.lastname: Hassanshahi
authors.affiliation: Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou, China.
authors.forename: Ke-Ming
authors.initials: KM
authors.lastname: Chen
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yangli
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Orthopaedic Surgery, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Foster
authors.affiliation: Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Rosen
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia.
authors.forename: Jiake
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
authors.forename: Cory J
authors.initials: CJ
authors.lastname: Xian
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D001861:Bone Regeneration / Q000502:physiology*; D002356:Cartilage / Q000378:metabolism*; D006132:Growth Plate / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; D020933:Neurotrophin 3; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3
keywords: BMP-2; BONE REPAIR; GROWTH PLATE; NEUROTROPHIC FACTOR; NEUROTROPHIN-3; VEGF