Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

NT-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats (#154)

Yu-Wen Su 1 , Rosa Chung 1 , Chun-Sheng Ruan 1 , Shek Man Chim 2 , Vincent Kuek 2 , Prem Dwivedi 1 , Mohammadhossein Hassanshahi 1 , Bruce K Foster 3 , Xin-Fu Zhou 1 , Jiake Xu 2 , Cory J Xian 1
  1. Sansom Institute for Health Research, & School of Pharmacy and Medical Sciences, University of South Australia, ADELAIDE, SA, Australia
  2. School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA
  3. Department of Orthopaedic Surgery, Women’s and Children’s Hospital, North Adelaide, SA, Australia

Injured growth plate is often repaired by bony tissue causing bone growth defects, for which the mechanisms remain unclear. Since neurotrophins have been implicated in bone fracture repair, here we investigated their potential roles in growth plate and bone 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, while 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 while 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, since 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.