Drug Design, Development and Therapy (Apr 2019)

A novel hybrid compound LLP2A-alendronate accelerates open fracture healing in a rabbit model

  • Wang Z,
  • Zhao Y,
  • Zhang D,
  • Qi B,
  • Xiao W,
  • Hu X,
  • Yu A

Journal volume & issue
Vol. Volume 13
pp. 1077 – 1086

Abstract

Read online

Zheng Wang, Yong Zhao, Dong Zhang, Baiwen Qi, Weidong Xiao, Xiang Hu, Aixi Yu Department of Orthopaedic Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, People’s Republic of China Purpose: LLP2A-alendronate (LLP2A-Ale) is a novel bone-seeking compound that recruits mesenchymal stem cells to the bone surface and stimulates bone formation. The purpose of this study was to investigate the efficacy of LLP2A-Ale in the treatment of rabbit open fracture.Methods: Thirty New Zealand White rabbits underwent radius mid-diaphyseal osteotomy and were randomly divided into control and treatment groups with fifteen rabbits in each group. The treatment group received only one injection of LLP2A-Ale (dosage 125 µg/kg), whereas the control group received one injection of PBS. X-ray images were taken to observe the course of fracture healing at 2, 4 and 6 weeks after treatment. Rabbits were sacrificed at 4 and 6 weeks post treatment. Calluses were then harvested and were subjected to histology, immunohistochemistry, molecular biology techniques and biomechanical test.Results: X-ray images showed that the LLP2A-Ale group exhibited abundant callus formation, stronger bony callus remodeling and earlier marrow cavity recanalization compared to the control group in a time-dependent manner. Histomorphological analysis revealed an advance in woven formation at 4 weeks and lamellar bone formation at 6 weeks in the LLP2A-Ale group. Moreover, gene and protein levels suggested that LLP2A-Ale promoted osteogenesis and angiogenesis probably via upregulating the expression of osteogenesis factors (including bone morphogenetic protein 2 and Runt-related transcription factor 2) and angiogenesis factors (vascular endothelial growth factor). Besides, the radius callus biomechanical properties were significantly enhanced in the LLP2A-Ale group compared with the control group at 6 weeks.Conclusion: LLP2A-Ale can significantly promote open fracture healing in the rabbit model, probably through enhancing osteogenesis and angiogenesis. Keywords: osteogenesis drug, fracture healing, angiogenesis, osteogenesis, rabbit fracture model

Keywords