Parathyroid hormone-related protein (PTHrP) modulates adhesion, migration and invasion in bone tumor cells

Parathyroid-hormone-related protein (PTHrP) has been shown to be an important factor in osteolysis in the setting of metastatic carcinoma to the bone. However, PTHrP may also be central in the setting of primary bone tumors. Giant cell tumor of bone (GCT) is an aggressive osteolytic bone tumor characterized by osteoclast-like giant cells that are recruited by osteoblast-like stromal cells. The stromal cells of GCT are well established as the only neoplastic element of the tumor, and we have previously shown that PTHrP is highly expressed by these cells both in vitro and in vivo. We have also found that the stromal cells exposed to a monoclonal antibody to PTHrP exhibited rapid plate detachment and quickly died in vitro. Therefore, PTHrP may serve in an autocrine manner to increase cell proliferation and promote invasive properties in GCT. The purpose of this study was to use transcriptomic microarrays and functional assays to examine the effects of PTHrP neutralization on cell adhesion, migration and invasion. Microarray and proteomics data identified genes that were differentially expressed in GCT stromal cells under various PTHrP treatment conditions. Treatment of GCT stromal cells with anti-PTHrP antibodies showed a change in the expression of 13 genes from the integrin family relative to the IgG control. Neutralization of PTHrP reduced cell migration and invasion as evidenced by functional assays. Adhesion and anoikis assays demonstrated that although PTHrP neutralization inhibits cell adhesion properties, cell detachment related to PTHrP neutralization did not result in associated cell death, as expected in mesenchymal stromal cells. Based on the data presented herein, we conclude that PTHrP excreted by GCT stromal cells increases bone tumor cell local invasiveness and migration.