VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice

Niida, Shumpei; Kondo, Takako; Hiratsuka, Sachie; Hayashi, S.; Amizuka, Norio; Noda, Tetsuo; Ikeda, Kyoji; Shibuya, Masabumi

doi:10.1073/pnas.0503544102

Cited by 107 publications

(86 citation statements)

References 41 publications

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“…VEGF may stimulate the growth and IL-34 synthesis of vascular endothelial cells. Consistent with the previous reports (11,12), the injection of VEGF-A 120 (VEGF 120 ) into CSF-1 op/op mice increased the appearance of TRAP(+) osteoclasts (Fig. S3A).…”

Section: Resultssupporting

confidence: 81%

“…The administration of VEGF improved the phenotype of osteopetrosis in CSF-1 op/op mice (11,12), and a deficiency of VEGFR1 worsened it (12). VEGF may stimulate the growth and IL-34 synthesis of vascular endothelial cells.…”

Section: Resultsmentioning

confidence: 99%

“…Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9,10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11,12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).…”

Section: ] (1 2)mentioning

confidence: 99%

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Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Osteoclasts are generated from monocyte/macrophage-lineage precursors in response to colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). CSF-1-mutated CSF-1 op/op mice as well as RANKL −/− mice exhibit osteopetrosis (OP) caused by osteoclast deficiency. We previously identified RANKL receptor (RANK)/CSF-1 receptor (CSF-1R) double-positive cells as osteoclast precursors (OCPs), which existed in bone in RANKL −/− mice. Here we show that OCPs do not exist in bone but in spleen in CSF-1 op/op mice, and spleen acts as their reservoir. IL-34, a newly discovered CSF-1R ligand, was highly expressed in vascular endothelial cells in spleen in CSF-1 op/op mice. Vascular endothelial cells in bone also expressed IL-34, but its expression level was much lower than in spleen, suggesting a role of IL-34 in the splenic generation of OCPs. Splenectomy (SPX) blocked CSF-1-induced osteoclastogenesis in CSF-1 op/op mice. Osteoclasts appeared in aged CSF-1 op/op mice with up-regulation of IL-34 expression in spleen and bone. Splenectomy blocked the age-associated appearance of osteoclasts. The injection of 2-methylene-19-nor-(20S)-1α,25(OH) 2 D 3 (2MD), a potent analog of 1α,25-dihidroxyvitamin D 3 , into CSF-1 op/op mice induced both hypercalcemia and osteoclastogenesis. Administration of 2MD enhanced IL-34 expression not only in spleen but also in bone through a vitamin D receptor-mediated mechanism. Either splenectomy or siRNA-mediated knockdown of IL-34 suppressed 2MD-induced osteoclastogenesis. These results suggest that IL-34 plays a pivotal role in maintaining the splenic reservoir of OCPs, which are transferred to bone in response to diverse stimuli, in CSF-1 op/op mice. The present study also suggests that the IL-34 gene in vascular endothelial cells is a unique target of vitamin D. CSF-1 is the most potent growth factor for monocytes/macrophages (3), but its synthesis by osteoblasts occurs independently of PTH and 1α,25(OH) 2 D 3 (2). CSF-1 op/op mice cannot produce a functionally active CSF-1 (4), and therefore, exhibit monocytopenia and osteopetrosis (OP) (5, 6). However, several curious phenomena have been observed in CSF-1 op/op mice. First, osteoclasts are totally absent in young CSF-1 op/op mice, but appear in aged CSF-1 op/op mice (7). Second, osteopetrotic characteristics of CSF-1R −/− mice are more severe than those of CSF-1 op/op mice (8). Third, F4/80 + [F4/80(+)] macrophages exist in the splenic red pulp in CSF-1 op/op mice as well as in WT mice, and their number is regulated by a mechanism independently of CSF-1 (9, 10). Fourth, the administration of vascular endothelial growth factor (VEGF) rescues osteopetrosis in CSF-1 op/op mice (11, 12), but VEGF cannot substitute for CSF-1 to induce osteoclast formation in vitro (13).Recently, Lin et al. (14) discovered IL-34, as a new ligand for CSF-1R. The amino acid sequence of IL-34 was quite different from that of CSF-1, but IL-34 promoted macrophage colony formation like CSF-1 did. IL-34 was specifically expressed in splen...

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: ] (1 2)mentioning

confidence: 99%

See 1 more Smart Citation

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Nakamichi¹,

Mizoguchi²,

Arai³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…23,24 Conflicting evidence exists as to whether VEGF-A can support osteoclast formation. [17][18][19]21,22 Our findings are in agreement with studies showing that VEGF-A can correct the defect in op/op mice and support a role for VEGF-A in osteoclast formation. Although VEGF-A has previously been reported to support human osteoclast formation in vitro by Aldridge et al, 21 this was not conclusively shown as osteoclastogenesis was not determined in the presence of an anti-M-CSF antibody and resorption was noted in negative control cultures.…”

Section: Discussionsupporting

confidence: 82%

“…This was confirmed in several studies where hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A), placental growth factor (PlGF) and FLT3 ligand (FL) were shown to be capable of supporting osteoclastogenesis in the absence of M-CSF. [16][17][18][19] These growth factors are abundant and widely distributed in human tissues and are thought to have a role in several neoplastic and inflammatory conditions, which affect bone and joint, including GCTB. 20 The effect of potential M-CSF substitute growth factors on human osteoclast formation and resorption is not well defined.…”

mentioning

confidence: 99%

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Taylor

Kashima

Knowles

et al. 2012

Laboratory Investigation

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Giant cell tumour of bone (GCTB) is a primary bone tumour that contains numerous very large, hyper-nucleated osteoclastic giant cells. Osteoclasts form from CD14 þ monocytes and macrophages in the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). GCTB contains numerous growth factors, some of which have been reported to influence osteoclastogenesis and resorption. We investigated whether these growth factors are capable of substituting for M-CSF to support osteoclast formation from cultured human monocytes and whether they influence osteoclast cytomorphology and resorption. Vascular endothelial growth factor-A (VEGF-A), VEGF-D, FLT3 ligand (FL), placental growth factor (PlGF) and hepatocyte growth factor (HGF) supported RANKL-induced osteoclastogenesis in the absence of M-CSF, resulting in the formation of numerous TRAP þ multinucleated cells capable of lacunar resorption. Monocytes cultured in the presence of M-CSF, HGF, VEGF-A and RANKL together resulted in the formation of very large, hyper-nucleated (GCTB-like) osteoclasts that were hyper-resorptive. M-CSF and M-CSF substitute growth factors were identified immunohistochemically in GCTB tissue sections and these factors stimulated the resorption of osteoclasts derived from a subset of GCTBs. Our findings indicate that there are growth factors that are capable of substituting for M-CSF to induce human osteoclast formation and that these factors are present in GCTB where they influence osteoclast cytomorphology and have a role in osteoclast formation and resorption activity. The osteoclast is a multinucleated cell, which is formed from circulating mononuclear phagocyte precursors derived from the bone marrow. 1,2 It exhibits a number of specialised cytochemical and functional features, including the ability to carry out lacunar bone resorption. Increased osteoclast formation and activity is seen in a number of osteolytic bone and joint conditions, including notably giant cell tumour of bone (GCTB), a primary bone tumour, which contains numerous, very large, often hyper-nucleated osteoclastic giant cells that effect a considerable amount of bone resorption. 3,4 Osteoclast differentiation from monocyte or macrophage precursors requires the presence of receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). 5 The importance of M-CSF in osteoclast formation is evidenced by the fact that in op/op osteopetrotic mice, which have a mutation in the M-CSF gene, very few osteoclasts are found in bone and there is markedly decreased bone resorption. 6,7 M-CSF promotes several aspects of osteoclastogenesis including the proliferation and fusion of osteoclast precursors as well as osteoclasts and the expression of the RANKL receptor by these cells. [8][9][10] The effect of M-CSF on mature osteoclast resorption activity is controversial with both a decrease and increase in lacunar resorption being reported. [11][12][13] Although bone resorption is gre...

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Angiogenic/osteogenic response of BMMSCs on bone‐derived scaffold: Effect of hypoxia and role of PI3K/Akt‐mediated VEGF‐VEGFR pathway

Zhou

Guan

et al. 2014

Biotechnology Journal

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Bone tissue deficiency is a common clinical challenge. Tissue-engineered bone constructs are an effective approach for the repair of orthopedic bone defects. Mimicking the essential components of the in vivo microenvironment is an efficient way to develop functional constructs. In this study, bone marrow-derived mesenchymal stromal cells (BMMSCs) were seeded into bone-derived scaffolds, a material with similar structure to natural bone. This was done under hypoxic conditions, an environment that imitates that experienced by BMMSCs in vivo. Our data indicate that hypoxia (5% O2 ) significantly increases the proliferation of BMMSCs seeded in scaffolds. As reflected by highly expressed osteogenesis- and angiogenesis-associated biomarkers, including vascular endothelial growth factor (VEGF), RUNX2, bone morphogenetic protein-2/4 and osteopontin, hypoxia also significantly increases the osteogenic and angiogenic responses of BMMSCs seeded into bone-derived scaffold composites. PI3K/Akt-mediated regulation of VEGF-activated VEGFR1/2 signaling is important for hypoxia-induced proliferative/osteogenic/angiogenic responses in BMMSC cellular scaffolds. The combination of bone-derived scaffolds and hypoxia is conducive to the differentiation of BMMSCs into functional tissue-engineered scaffold composites.

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VEGF receptor 1 signaling is essential for osteoclast development and bone marrow formation in colony-stimulating factor 1-deficient mice

Cited by 107 publications

References 41 publications

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

Spleen serves as a reservoir of osteoclast precursors through vitamin D-induced IL-34 expression in osteopetrotic op/op mice

VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology

Angiogenic/osteogenic response of BMMSCs on bone‐derived scaffold: Effect of hypoxia and role of PI3K/Akt‐mediated VEGF‐VEGFR pathway

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