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J Bone Miner Res. 2016 Jun;31(6):1258-74. doi: 10.1002/jbmr.2786. Epub 2016 Feb 16.

Neurotrophin-3 Induces BMP-2 and VEGF Activities and Promotes the Bony Repair of Injured Growth Plate Cartilage and Bone in Rats.

Author information

1
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia.
2
School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia.
3
Institute of Orthopaedics, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou, China.
4
Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burns, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, China.
5
Department of Orthopaedic Surgery, Women's and Children's Hospital, North Adelaide, Australia.
6
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA, USA.

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.

KEYWORDS:

BMP-2; BONE REPAIR; GROWTH PLATE; NEUROTROPHIC FACTOR; NEUROTROPHIN-3; VEGF

PMID:
26763079
DOI:
10.1002/jbmr.2786
[Indexed for MEDLINE]
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