VEGF-C, a Lymphatic Growth Factor, Is a RANKL Target Gene in Osteoclasts That Enhances Osteoclastic Bone Resorption through an Autocrine Mechanism

Osteoclasts are bone-resorbing cells, but they also secrete and respond to cytokines. Here, we test the hypothesis that osteoclasts secrete the lymphatic growth factor, VEGF-C, to increase their resorptive activity. Osteoclasts and osteoclast precursors were generated by culturing splenocytes with m...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2008-05, Vol.283 (19), p.13491-13499
Main Authors: Zhang, Qian, Guo, Ruolin, Lu, Yan, Zhao, Lan, Zhou, Quan, Schwarz, Edward M., Huang, Jing, Chen, Di, Jin, Zheng-Gen, Boyce, Brendan F., Xing, Lianping
Format: Article
Language:English
Subjects:
Animals
Autocrine Communication - drug effects
Bone Resorption - genetics
Bone Resorption - metabolism
Gene Expression Regulation - drug effects
Lymphocytes - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoclasts - drug effects
Osteoclasts - metabolism
Promoter Regions, Genetic - genetics
RANK Ligand - pharmacology
Signal Transduction
src-Family Kinases - metabolism
Vascular Endothelial Growth Factor C - genetics
Vascular Endothelial Growth Factor C - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Osteoclasts are bone-resorbing cells, but they also secrete and respond to cytokines. Here, we test the hypothesis that osteoclasts secrete the lymphatic growth factor, VEGF-C, to increase their resorptive activity. Osteoclasts and osteoclast precursors were generated by culturing splenocytes with macrophage colony-stimulating factor and RANKL from wild-type, NF-κBp50-/-/p52-/-, and Src-/- mice. Expression of VEGFs was measured by real time reverse transcription-PCR, Western blotting, and immunostaining. The effect of VEGF-C signaling on osteoclast function was determined by osteoclastogenesis and pit assays. RANKL increased the expression of VEGF-C but not of other VEGFs in osteoclasts and their precursors. RANKL-induced VEGF-C expression was reduced in NF-κBp50-/-/p52-/- precursors or wild-type cells treated with an NF-κB inhibitor. VEGF-C directly stimulated RANKL-mediated bone resorption, which was reduced by the VEGF-C-specific receptor blocker, VEGFR3:Fc. Osteoclasts express VEGFR3, and VEGF-C stimulated Src phosphorylation in osteoclasts. VEGF-C-mediated bone resorption was abolished in Src-/- osteoclasts or cells treated with an Src inhibitor. We conclude that RANKL stimulates osteoclasts and their precursors to release VEGF-C through an NF-κB-dependent mechanism, indicating that VEGF-C is a new RANKL target gene in osteoclasts and functions as an autocrine factor regulating osteoclast activity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M708055200