title: Molecular signaling pathways mediating osteoclastogenesis induced by prostate cancer cells.
abstract: BACKGROUND
  Advanced prostate cancer commonly metastasizes to bone leading to osteoblastic and osteolytic lesions. Although an osteolytic component governed by activation of bone resorbing osteoclasts is prominent in prostate cancer metastasis, the molecular mechanisms of prostate cancer-induced osteoclastogenesis are not well-understood.
  
  
  METHODS
  We studied the effect of soluble mediators released from human prostate carcinoma cells on osteoclast formation from mouse bone marrow and RAW 264.7 monocytes.
  
  
  RESULTS
  Soluble factors released from human prostate carcinoma cells significantly increased viability of naïve bone marrow monocytes, as well as osteoclastogenesis from precursors primed with receptor activator of nuclear factor κ-B ligand (RANKL). The prostate cancer-induced osteoclastogenesis was not mediated by RANKL as it was not inhibited by osteoprotegerin (OPG). However inhibition of TGFβ receptor I (TβRI), or macrophage-colony stimulating factor (MCSF) resulted in attenuation of prostate cancer-induced osteoclastogenesis. We characterized the signaling pathways induced in osteoclast precursors by soluble mediators released from human prostate carcinoma cells. Prostate cancer factors increased basal calcium levels and calcium fluctuations, induced nuclear localization of nuclear factor of activated t-cells (NFAT)c1, and activated prolonged phosphorylation of ERK1/2 in RANKL-primed osteoclast precursors. Inhibition of calcium signaling, NFATc1 activation, and ERK1/2 phosphorylation significantly reduced the ability of prostate cancer mediators to stimulate osteoclastogenesis.
  
  
  CONCLUSIONS
  This study reveals the molecular mechanisms underlying the direct osteoclastogenic effect of prostate cancer derived factors, which may be beneficial in developing novel osteoclast-targeting therapeutic approaches.
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Rafiei
authors.affiliation: Department of Anatomy and Cell Biology, Faculty of Medicine, 3640 University Street, Montreal, Quebec H3A 2B2, Canada. svetlana.komarova@mcgill.ca.
authors.forename: Svetlana V
authors.initials: SV
authors.lastname: Komarova
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D020013:Calcium Signaling; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D017077:Culture Media, Conditioned; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D017077:Culture Media, Conditioned; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human