title: PTHrP increases RANKL expression by stromal cells from giant cell tumor of bone.
abstract: Giant cell tumor of bone (GCT) presents with numerous osteoclast-like multinucleated giant cells that are principally responsible for the extensive bone resorption by the tumor. Although the precise etiology of GCT remains uncertain, the accumulation of giant cells is partially due to the high expression of the receptor activator of nuclear factor-κB ligand (RANKL) from the neoplastic stromal cells. Here, we have investigated whether parathyroid hormone-related protein (PTHrP) plays a role in the pathogenesis of GCT. Immunohistochemistry results revealed PTHrP expression in the stromal cells of the tumor, and that its receptor, the parathyroid hormone type 1 receptor (PTH1R), is expressed by both the stromal cells and giant cells. PCR and Western blot analyses confirmed the expression of PTHrP and PTH1R by isolated stromal cells from five patients presenting with GCT. Treatment of GCT stromal cells with varying concentrations of PTHrP (1-34) significantly increased both RANKL gene expression and the number of multinucleated cells formed from RAW 264.7 cells in co-culture experiments, whereas inhibition of PTHrP with a neutralizing antibody decreased RANKL gene expression. These results suggest that PTHrP is expressed within GCT by the stromal cells and can contribute to the abundant RANKL expression and giant cell formation within the tumor.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Cowan
authors.forename: Gurmit
authors.initials: G
authors.lastname: Singh
authors.forename: Michelle
authors.initials: M
authors.lastname: Ghert
mesh_terms: D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015726:Giant Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D044162:Parathyroid Hormone-Related Protein / Q000276:immunology / Q000494:pharmacology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; C473449:PTH1R protein, human; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D044168:Receptor, Parathyroid Hormone, Type 1; C505688:TNFSF11 protein, human