VEGF, FLT3 ligand, PlGF and HGF can substitute for M-CSF to induce human osteoclast formation: implications for giant cell tumour pathobiology.
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+ 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+ 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.
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK.
Richard M
RM
Taylor
Takeshi G
TG
Kashima
Helen J
HJ
Knowles
Nicholas A
NA
Athanasou
D000135:Acid Phosphatase / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D018212:Giant Cell Tumor of Bone / Q000378:metabolism* / Q000473:pathology; D015726:Giant Cells / Q000378:metabolism / Q000473:pathology; D006133:Growth Substances / Q000378:metabolism* / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism / Q000494:pharmacology
D014408:Biomarkers, Tumor; D006133:Growth Substances; D007527:Isoenzymes; D008565:Membrane Proteins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D053245:RANK Ligand; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; C084881:flt3 ligand protein; D000072483:Placenta Growth Factor; D017228:Hepatocyte Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase