Fucoidan‐induced osteogenic differentiation promotes angiogenesis by inducing vascular endothelial growth factor secretion and accelerates bone repair

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.

Effect of Enzymatically Extracted Fucoidans on Angiogenesis and Osteogenesis in Primary Cell Culture Systems Mimicking Bone Tissue Environment

“…Various studies already claimed that fucoidans interfere with the formation of blood vessels. However, due to different experimental set-ups and fucoidans, the results of these studies vary tremendously from anti- [ 12 , 22 , 23 , 24 , 25 , 26 ] to pro-angiogenic [ 27 , 28 , 29 , 30 ] and yet it is not finally clarified which chemical requirements a fucoidan extract must meet to achieve specific bioactivities.…”

Fucoidan Structure and Activity in Relation to Anti-Cancer Mechanisms

“…The binding of VEGF165 to different VEGF receptors was strongly increased upon fucoidan treatment [170]. Furthermore, fucoidan ( S. japonica) stimulated in vitro osteoblast differentiation by inducing the expression of VEGF in mesenchymal stem cells [171].…”

Fucoidan inhibits tooth movement by promoting restorative macrophage polarization through the STAT3 pathway

“…Fucoidan has been shown to increase the messenger RNA expression of Bmp‐2, ALP, osteocalcin, and osteonectin, which can increase bone density in mice and have an anabolic effect on bone mineralization in vivo (Hwang et al, 2016). Kim, Yang, You, Shin, and Lee (2018) found that angiogenesis and osteogenesis were promoted by fucoidan in a rabbit model of a calvarial bone defect. Our study showed that the bone mineral density of the fucoidan‐treated mice was significantly higher than that of the control group at Day 14, which was consistent with previous studies.…”