Vascular endothelial growth factor-C induces osteogenic differentiation of human mesenchymal stem cells through the ERK and RUNX2 pathway.
Vascular endothelial cell growth factor C (VEGF-C) is a member of the VEGF family and plays a role in a variety of biological activities including lymphangiogenesis, angiogenesis, and neurogenesis through VEGF receptor 2 (VEGFR2) and 3 (VEGFR3). However, it has not been elucidated whether VEGF-C promotes osteogenic differentiation. Herein, we investigated the effects of VEGF-C on osteogenic differentiation in human mesenchymal stem cells (MSCs) and evaluated the underlying molecular mechanisms. VEGF-C treatment significantly increased RUNX2 expression, and led to the promotion of osteogenic marker gene expression and mineralization of MSCs. VEGF-C treatment induced the phosphorylation of VEGFR2 and VEGFR3 in MSCs. Treatment with the VEGFR3-specific ligand VEGF-C156S also promoted MSC mineralization. Furthermore, co-treatment with VEGFR2 and VEGFR3 kinase inhibitors blocked VEGF-C-induced MSC mineralization. VEGF-C treatment activated ERK signaling in MSCs, and inhibition of ERK signaling effectively suppressed VEGF-C-induced RUNX2 expression and mineralization. These results indicate that VEGF-C-induced MSC osteogenesis is mediated through VEGFR2 and VEGFR3, and followed the activation of the ERK/RUNX2 signaling pathway.
Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan; Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan.
Juri
J
Murakami
Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan. Electronic address: masai@dent.kagoshima-u.ac.jp.
Masakazu
M
Ishii
Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan.
Fumio
F
Suehiro
Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan.
Kiyohide
K
Ishihata
Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan.
Norifumi
N
Nakamura
Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, 890-8544, Japan.
Masahiro
M
Nishimura
D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3
ERK; Mesenchymal stem cells; Osteogenesis; RUNX2; VEGF-C