Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma

Rui Yang, Bang H. Hoang, Tadahiko Kubo, Hirotaka Kawano, Alexander Chou, Rebecca Sowers, Andrew G. Huvos, Paul A. Meyers, John H. Healey, Richard Gorlick

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Osteosarcoma is the most common primary bone malignancy in children and is associated with rapid bone growth. Parathyroid hormone-related peptide (PTHrP) signaling via parathyroid hormone Type 1 receptor (PTHR1) is important for skeletal development and is involved in bone metastases in other tumors. The aim of this study was to investigate the status of PTHrP/PTHR1 and its possible role in osteosarcoma. In a preliminary screening, a higher level of PTHR1 mRNA, but not PTHrP, was found in 4 osteosarcoma xenografts as compared with 4 standard cell lines, or 5 patient derived cell lines (p < 0.05) using quantitative RT-PCR. It was therefore extended to 55 patient specimens, in which a significantly higher level of PTHR1 mRNA was detected in metastatic or relapsed samples than those from primary sites (p < 0.01). Cell behavior caused by PTHR1 overexpression was further studied in vitro using PTHR1 transfected HOS cell line as a model. Over-expression of PHTR1 resulted in increased proliferation, motility and Matrigel invasion without addition of exogenous PTHrP suggesting an autocrine effect. Importantly, the aggressiveness in PTHR1-expressing cells was completely reversed by RNAi mediated gene knockdown. In addition, PTHR1 overexpression led to delayed osteoblastic differentiation and upregulation of genes involved in extracellular matrix production, such as TGF-β1 and connective tissue growth factor. When cocultured with bone marrow derived monocytes, PTHR1 transfected HOS cells induced a greater number of osteoclasts. This study suggests that PTHR1 over-expression may promote osteosarcoma progression by conferring a more aggressive phenotype, and forming a more favorable microenvironment.

Original languageEnglish (US)
Pages (from-to)943-954
Number of pages12
JournalInternational Journal of Cancer
Volume121
Issue number5
DOIs
StatePublished - Sep 1 2007

Keywords

  • Metastasis
  • Osteosarcoma
  • Parathyroid hormone Type 1 receptor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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