Fucoidan-induced Osteogenic Differentiation Promotes Angiogenesis by Inducing Vascular Endothelial Growth Factor Secretion and Accelerates Bone Repair

J Tissue Eng Regen Med. 2018 Mar;12(3):e1311-e1324. doi: 10.1002/term.2509. Epub 2017 Oct 4.

Abstract

Osteogenesis and angiogenesis, including cell-cell communication between blood vessel cells and bone cells, are essential for bone repair. Fucoidan is a chemical compound that has a variety of biological activities. It stimulates osteoblast differentiation in human mesenchymal stem cells (MSCs), which in turn induces angiogenesis. However, the mechanism by which this communication between osteoblasts and endothelial cells is mediated remains unclear. Thus, the aim of this study was to clarify the relationship between fucoidan-induced osteoblastic differentiation in MSCs and angiogenesis in endothelial cells. First, the effect was confirmed of fucoidan on osteoblast differentiation in MSCs and obtained conditioned media from these cells (Fucoidan-MSC-CM). Next, the angiogenic activity of Fucoidan-MSC-CM was investigated and it was found that it stimulated angiogenesis, demonstrated by proliferation, tube formation, migration and sprout capillary formation in human umbilical vein endothelial cells. Messenger ribonucleic acid expression and protein secretion of vascular endothelial growth factor (VEGF) were dramatically increased during fucoidan-induced osteoblast differentiation and that its angiogenic activities were reduced by a VEGF/VEGF receptor-specific binding inhibitor. Furthermore, Fucoidan-MSC-CM increased the phosphorylation of mitogen-activated protein kinase and PI3K/AKT/eNOS signalling pathway, and that its angiogenic effects were markedly suppressed by SB203580 and AKT 1/2 inhibitor. Finally, an in vivo study was conducted and it was found that fucoidan accelerated new blood vessel formation and partially promoted bone formation in a rabbit model of a calvarial bone defect. This is the first study to investigate the angiogenic effect of fucoidan-induced osteoblastic differentiation through VEGF secretion, suggesting the therapeutic potential of fucoidan for enhancing bone repair.

Keywords: angiogenesis; bone regeneration; fucoidan; mesenchymal stem cell; osteogenic differentiation; vascular endothelial growth factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Regeneration / drug effects*
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Culture Media, Conditioned / pharmacology
  • Disease Models, Animal
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Neovascularization, Physiologic / drug effects*
  • Osteoblasts / cytology
  • Osteogenesis / drug effects*
  • Phosphorylation / drug effects
  • Polysaccharides / pharmacology*
  • Rabbits
  • Skull / drug effects
  • Skull / pathology
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Culture Media, Conditioned
  • Polysaccharides
  • Vascular Endothelial Growth Factor A
  • fucoidan