RGD Reference Report - A novel function for platelet-derived growth factor D: induction of osteoclastic differentiation for intraosseous tumor growth. - Rat Genome Database

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

Authors: Huang, W  Fridman, Y  Bonfil, R D  Ustach, C V  Conley-LaComb, M K  Wiesner, C  Saliganan, A  Cher, M L  Kim, H-R C 
Citation: Huang W, etal., Oncogene. 2012 Oct 18;31(42):4527-35. doi: 10.1038/onc.2011.573. Epub 2011 Dec 12.
RGD ID: 13506772
Pubmed: PMID:22158043   (View Abstract at PubMed)
PMCID: PMC3482867   (View Article at PubMed Central)
DOI: DOI:10.1038/onc.2011.573   (Journal Full-text)

Although increasing evidence suggests a critical role for platelet-derived growth factor (PDGF) receptor ß (ß-PDGFR) signaling in prostate cancer (PCa) progression, the precise roles of ß-PDGFR and PDGF isoform-specific cell signaling have not been delineated. Recently, we identified the PDGF-D isoform as a ligand for ß-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 ß-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Bone Metastasis  IMP 13506772associated with prostate carcinomaRGD 
Bone Metastasis  ISOPDGFD (Homo sapiens)13506772; 13506772associated with prostate carcinomaRGD 

Objects Annotated

Genes (Rattus norvegicus)
Pdgfd  (platelet derived growth factor D)

Genes (Mus musculus)
Pdgfd  (platelet-derived growth factor, D polypeptide)

Genes (Homo sapiens)
PDGFD  (platelet derived growth factor D)


Additional Information