Possible Involvement of the Vascular Endothelial Growth Factor-Flt-1-Focal Adhesion Kinase Pathway in Chemotaxis and the Cell Proliferation of Osteoclast Precursor Cells in Arthritic Joints

Matsumoto, Yoshihiro; Tanaka, Kazuhiro; Hirata, Go; Hanada, Masuo; Matsuda, Shinya; Shuto, Toshihide; Iwamoto, Yukihide

doi:10.4049/jimmunol.168.11.5824

Cited by 73 publications

(68 citation statements)

References 45 publications

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“…An injection of VEGF induces osteoclast recruitment in a manner similar to M-CSF injection (Niida et al, 1999). Vascular endothelial growth factor induces preosteoclasts from arthritic joints to differentiate, migrate and proliferate and this seems to be mediated by VEGFR1 (Matsumoto et al, 2002). Osteoclastic induction has also been shown to be increased around moving teeth when VEGF is administered locally (Kaku et al, 2001).…”

Section: Discussionmentioning

confidence: 97%

Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone

Aldridge

Lennard

et al. 2005

Br J Cancer

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Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that is expressed highly in many solid tumours often correlating with a poor prognosis. In this study, we investigated the expression of VEGF and its receptors in bone metastases from primary human breast tumours and further characterised its effects on osteoclasts in vitro. Breast cancer metastases to bone were immunohistochemically stained for VEGF, its receptors VEGFR1 and 2 (vascular endothelial growth factor receptor 1 and 2), demonstrating that breast cancer metastases express VEGF strongly and that surrounding osteoclasts express both VEGFR1 and VEGFR2. RAW 264.7 cells (mouse monocyte cell line) and human peripheral blood mononuclear cells (PBMCs) were cultured with VEGF, RANKL and M-CSF. VEGF and RANKL together induced differentiation of multinucleated, tartrate-resistant acid phophatase (TRAP)-positive cells in similar numbers to M-CSF and RANKL. The PBMCs were also able to significantly stimulate resorption of mineralised matrix after treatment with M-CSF with RANKL and VEGF with RANKL. We have shown that VEGF in the presence of RANKL supports PBMC differentiation into osteoclast-like cells, able to resorb substrate. Vascular endothelial growth factor may therefore play a role in physiological bone resorption and in pathological situations. Consequently, VEGF signalling may be a therapeutic target for osteoclast inhibition in conditions such as tumour osteolysis.

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Section: Discussionmentioning

confidence: 97%

Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone

Aldridge

Lennard

et al. 2005

Br J Cancer

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“…A previous report has shown that no osteoclast precursor cells are found in PDLs before the application of orthodontic force but osteoclast precursor cells rapidly increase one day after the application of force (Xie et al, 2008). Given that VEGF is a well-known chemotactic factor for osteoclast precursor cells (Matsumoto et al, 2002), it is likely that hypoxia-induced VEGF secretion from compression side PDLFs may be involved in the recruitment of osteoclast precursor cells from the surrounding alveolar bone to the PDL tissue. Subsequently, osteoclast differentiation may be induced by the additive actions of RANKL and VEGF.…”

Section: A B Cmentioning

confidence: 99%

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Park

Baek

Lee

et al. 2011

Molecules and Cells

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During orthodontic tooth movement, local hypoxia and enhanced osteoclastogenesis are observed in the compression side of periodontal tissues. The receptor activator of nuclear factor-κB ligand (RANKL) is an osteoblast/ stromal cell-derived factor that is essential for osteoclastogenesis. In this study, we examined the effect of hypoxia on RANKL expression in human periodontal ligament fibroblasts (PDLFs) to investigate the relationship between local hypoxia and enhanced osteoclastogenesis in the compression side of periodontal tissues. Hypoxia significantly enhanced the levels of RANKL mRNA and protein as well as hypoxia inducible factor-1α (HIF-1α) protein in PDLFs. Constitutively active HIF-1α alone significantly increased the levels of RANKL expression in PDLFs under normoxic conditions, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL expression. To investigate further whether HIF-1α directly regulates RANKL transcription, a luciferase reporter assay was performed using the reporter vector containing the RANKL promoter sequence. Exposure to hypoxia or overexpression of constitutively active HIF-1α significantly increased RANKL promoter activity, whereas dominant negative HIF-1α blocked hypoxia-induced RANKL promoter activity. Furthermore, mutations of putative HIF-1α binding elements in RANKL promoter prevented hypoxia-induced RANKL promoter activity. The results of chromatin immunoprecipitation showed that hypoxia or constitutively active HIF-1α increased the DNA binding of HIF-1α to RANKL promoter. These results suggest that HIF-1α mediates hypoxia-induced up-regulation of RANKL expression and that in compression side periodontal ligament, hypoxia enhances osteoclastogenesis, at least in part, via an increased RANKL expression in PDLFs.

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“…Functional VEGF-RII is overexpressed in the human RA synovium (18,19). Osteoclast precursors and osteoclast cells express VEGF-RI on their membranes in vitro, and VEGF mediates the recruitment, chemotaxis, and proliferation of osteoclast precursor cells, leading to bone destruction in vivo (20). Nothing is known about VEGF-RI or -RII expression by synovial cells.…”

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

Blockade of Vascular Endothelial Growth Factor Receptor I (VEGF-RI), but not VEGF-RII, Suppresses Joint Destruction in the K/BxN Model of Rheumatoid Arthritis

Bandt

Mahdi²,

Ollivier³

et al. 2003

The Journal of Immunology

116

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It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and semiquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.

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Possible Involvement of the Vascular Endothelial Growth Factor-Flt-1-Focal Adhesion Kinase Pathway in Chemotaxis and the Cell Proliferation of Osteoclast Precursor Cells in Arthritic Joints

Cited by 73 publications

References 45 publications

Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone

Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone

Hypoxia Inducible Factor-1α Directly Induces the Expression of Receptor Activator of Nuclear Factor-κB Ligand in Periodontal Ligament Fibroblasts

Blockade of Vascular Endothelial Growth Factor Receptor I (VEGF-RI), but not VEGF-RII, Suppresses Joint Destruction in the K/BxN Model of Rheumatoid Arthritis

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