Abstract
BackgroundGiant cell tumors (GCTs) of bone are primary benign bone tumors that are characterized by a high number of osteoclast-like multinuclear giant cells (MNCs). Recent studies suggest that the spindle-shaped stromal cells in GCTs are tumor cells, while monocyte-like cells and MNCs are reactive osteoclast precursor cells (OPCs) and osteoclasts (OCs), respectively. In this study, we investigated the pathogenesis of osteoclastic bone destruction in GCTs by focusing on the role of the vascular endothelial growth factor (VEGF)-Flt-1 (type-1 VEGF receptor)-focal adhesion kinase (FAK) pathway.MethodsThe motility of OPCs cells was assessed by a chemotaxis assay and the growth of OPCs was examined using a cell proliferation assay. The expression of VEGF and activation of Flt-1 and FAK in clinical GCT samples and in OPCs were detected by immunohistochemistry and immunoblotting. The correlation between the expression levels of activated Flt-1 and FAK and clinical stages of GCTs was investigated by immunohistochemistry.ResultsIn GCT samples, CD68, a marker of OPCs and OCs, co-localized with Flt-1. Conditioned media from GCT tissue (GCT-CM) enhanced the chemotaxis and proliferation of OPCs. GCT-CM also stimulated FAK activation in OPCs in vitro. Moreover, there was a correlation between the clinical stage of GCTs and the expression of tyrosine-phosphorylated Flt-1 and FAK.ConclusionsOur results suggest that the VEGF-Flt-1-FAK pathway is involved in the pathogenesis of bone destruction of GCTs.
Highlights
Giant cell tumors (GCTs) of bone are primary benign bone tumors that are characterized by a high number of osteoclast-like multinuclear giant cells (MNCs)
We previously reported that the vascular endothelial growth factor (VEGF)-Flt-1focal adhesion kinase (FAK) pathway may be involved in the chemotaxis and cell proliferation of osteoclast precursor cells (OPCs) and contribute to arthritic joint destruction [9]
In conclusion, our results suggest that the VEGF-Flt-1FAK pathway is potentially involved in recruiting OPCs in GCTs
Summary
Giant cell tumors (GCTs) of bone are primary benign bone tumors that are characterized by a high number of osteoclast-like multinuclear giant cells (MNCs). Primary cell cultures of GCTs revealed that the stromal cells are likely the proliferating cell type in GCTs. Recently, it was reported that these stromal cells secrete several cytokines and differentiation factors, including TGF-b [5], MCP-1[6], RANKL [7] and M-CSF [8]. It was reported that these stromal cells secrete several cytokines and differentiation factors, including TGF-b [5], MCP-1[6], RANKL [7] and M-CSF [8] These soluble factors could function as monocyte chemoattractants and stimulate osteoclast differentiation, suggesting that the stromal cells stimulate blood monocytes to migrate into the tumor tissue and enhance in situ osteoclastogenesis, leading to extended osteolysis by OCs
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