A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth

Oncogene. 2012 Oct 18;31(42):4527-35. doi: 10.1038/onc.2011.573. Epub 2011 Dec 12.

Abstract

Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor β (β-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of β-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for β-PDGFR in PCa and showed that PDGF-D is activated by serine protease-mediated proteolytic removal of the CUB domain in a two-step process, yielding first a hemidimer (HD) and then a growth factor domain dimer. Herein, we demonstrate that the expression of PDGF-D in human PCa LNCaP cells leads to enhanced bone tumor growth and bone responses in immunodeficient mice. Histopathological analyses of bone tumors generated by PDGF-D-expressing LNCaP cells (LNCaP-PDGF-D) revealed osteolytic and osteoblastic responses similar to those observed in human PCa bone metastases. Importantly, we discovered a novel function of PDGF-D in the regulation of osteoclast differentiation, independent of the RANKL/RANK signaling axis. Although both PDGF-B and -D were able to activate β-PDGFR, only PDGF-D was able to induce osteoclastic differentiation in vitro, and upregulate the expression and nuclear translocation of nuclear factor of activated T cells 1, a master transcription factor for osteoclastogenesis. Taken together, these results reveal a new function of PDGF-D as a regulator of osteoclastic differentiation, an activity critical for the establishment of skeletal metastatic deposit in PCa patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Phosphatase / genetics
  • Acid Phosphatase / metabolism
  • Animals
  • Blotting, Western
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Humans
  • Immunohistochemistry
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Lymphokines / genetics
  • Lymphokines / metabolism*
  • Lymphokines / pharmacology
  • Male
  • Mice
  • Mice, SCID
  • Mutation
  • NIH 3T3 Cells
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Platelet-Derived Growth Factor / genetics
  • Platelet-Derived Growth Factor / metabolism*
  • Platelet-Derived Growth Factor / pharmacology
  • Proto-Oncogene Proteins c-sis / metabolism
  • Proto-Oncogene Proteins c-sis / pharmacology
  • RANK Ligand / genetics
  • RANK Ligand / pharmacology
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Recombinant Proteins / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tartrate-Resistant Acid Phosphatase
  • Tibia / drug effects
  • Tibia / metabolism*
  • Tibia / pathology

Substances

  • Isoenzymes
  • Lymphokines
  • Pdgfd protein, mouse
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • RANK Ligand
  • Recombinant Proteins
  • Receptor, Platelet-Derived Growth Factor beta
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase