Fms-like tyrosine kinase (Flt)-4 signaling participates in osteoclast differentiation in osteopetrotic (op/op) mice.
Vascular endothelial growth factor (VEGF) induces osteoclast differentiation as well as neovascularization by binding to the fms-like tyrosine kinase (Flt)-1 and fetal liver kinase (Flk)-1 receptors. The Flt-4 receptor also plays an important role in angiogenesis and lymphangiogenesis. The purpose of this study was to investigate the functions of Flt-4 in the signaling pathway of osteoclast differentiation. We examined the expression of Flt-4 on osteoclast precursor cells (OCPs), and the ability of recombinant human (rh) VEGF-D, one of the ligands of Flt-4, to stimulate the phosphorylation of extracellular-regulated kinase1/2 (ERK1/2) and to activate the nuclear factor-kappa B (NF-kappaB) pathway in OCPs. The number of osteoclasts induced by injection of rhVEGF-D in osteopetrotic (op/op) mice was also evaluated in the absence or presence of neutralizing antibodies to Flt-4. Flt-4 expression was detected on OCPs at both gene and protein levels and stimulation of Flt-4 by rhVEGF-D might induce activation of mitogen-activated protein kinase (MAPK) and NF-kappaB pathways for induction of osteoclast differentiation. Moreover, the number of osteoclasts in op/op mice increased after injection of rhVEGF-D, but was significantly reduced by the injection of Flt-4 neutralizing antibodies. We have therefore shown that Flt-4 expressed on OCPs, might activate MAPK and NF-kappaB pathways and played an important role in osteoclast differentiation.
Tsuka
Natsumi
N
Department of Orthodontics and Craniofacial Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan. natsumi-t@hiroshima-u.ac.jp
Motokawa
Masahide
M
Kaku
Masato
M
Kawata
Toshitsugu
T
Fujita
Tadashi
T
Ohtani
Junji
J
Koseki
Hiroyuki
H
Sunagawa
Hiroko
H
Matsuda
Yayoi
Y
Abedini
Sara
S
Hayashi
Hidetaka
H
Tanne
Kazuo
K
D000818:Animals; D002454:Cell Differentiation; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D010022:Osteopetrosis / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism / Q000502:physiology*
D008024:Ligands; D016328:NF-kappa B; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3