Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation.
Vascular endothelial growth factor (VEGF)-D is a member of the VEGF family of angiogenic growth factors that recognizes and activates the vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 on blood and/or lymphatic vessels. We show that in the long bones of newborn mice, VEGF-D and VEGFR-3 are expressed in the osteoblasts of the growing plate. The treatment of primary human osteoblasts with recombinant VEGF-D induces the expression of osteocalcin and the formation of mineralized nodules in a dose-dependent manner. A monoclonal neutralizing antibody, anti-VEGF-D, or silencing of VEGFR-3 by lentiviral-mediated expression of VEGFR-3 small hairpin RNA affects VEGF-D-dependent osteocalcin expression and nodule formation. Moreover, in primary human osteoblasts, VEGF-D expression is under the control of VEGF, and inhibition of VEGF-D/VEGFR-3 signaling, by monoclonal antibodies or VEGFR-3 silencing, affects VEGF-dependent osteoblast differentiation. These experiments establish that VEGF-D/VEGFR-3 signaling plays a critical role in osteoblast maturation and suggest that VEGF-D is a downstream effector of VEGF in osteogenesis.
Orlandini
Maurizio
M
Dipartimento di Biologia Molecolare, Sezione Reumatologia, Universitá degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
Spreafico
Adriano
A
Bardelli
Monia
M
Rocchigiani
Marina
M
Salameh
Ahmad
A
Nucciotti
Sara
S
Capperucci
Caterina
C
Frediani
Bruno
B
Oliviero
Salvatore
S
D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology* / Q000502:physiology*; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000502:physiology*; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D042643:Vascular Endothelial Growth Factor D / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D042643:Vascular Endothelial Growth Factor D; D015675:Osteocalcin; D040321:Vascular Endothelial Growth Factor Receptor-3