title: Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-kappaB ligand pathway.
abstract: Bone is a common site of cancer metastasis. Breast, prostate, and lung cancers show a predilection to metastasize to bone. Recently, we reported that the chemokine interleukin 8 (IL-8) stimulates both human osteoclast formation and bone resorption. IL-8 mRNA expression was surveyed in a panel of human breast cancer lines MDA-MET, MDA-MB-231, MDA-MB-435, MCF-7, T47D, and ZR-75, and the human lung adenocarcinoma cell line A549. IL-8 mRNA expression was higher in cell lines with higher osteolytic potential in vivo. Human osteoclast formation was increased by MDA-MET or A549 cell-conditioned medium, but not by MDA-MB-231. Pharmacologic doses of receptor activator of nuclear factor-kappaB (RANK)-Fc or osteoprotogerin had no effect on the pro-osteoclastogenic activity of the conditioned medium; however, osteoclast formation stimulated by conditioned medium was inhibited 60% by an IL-8-specific neutralizing antibody. The data support a model in which tumor cells cause osteolytic bone destruction independently of the RANK ligand (RANKL) pathway. Tumor-produced IL-8 is a major contributor to this process. The role of secreted IL-8 isoforms was examined by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, which detected distinct IL-8 isoforms secreted by MDA-MET and MDA-231 cells, suggesting different pro-osteoclastogenic activities of the two IL-8-derived peptides. These data indicate that (a) osteoclast formation induced by MDA-MET breast cancer cells and A549 adenocarcinoma cells is primarily mediated by IL-8, (b) cell-specific isoforms of IL-8 with distinct osteoclastogenic activities are produced by tumor cells, and (c) tumor cells that support osteoclast formation independent of RANKL secrete other pro-osteoclastogenic factors in addition to IL-8.
authors.affiliation: Department of Orthopaedic Surgery, Center for Orthopaedic Research, Barton Research Institute, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
authors.forename: Manali S
authors.initials: MS
authors.lastname: Bendre
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Margulies
authors.forename: Brandon
authors.initials: B
authors.lastname: Walser
authors.forename: Nisreen S
authors.initials: NS
authors.lastname: Akel
authors.forename: Sudeepa
authors.initials: S
authors.lastname: Bhattacharrya
authors.forename: Robert A
authors.initials: RA
authors.lastname: Skinner
authors.forename: Frances
authors.initials: F
authors.lastname: Swain
authors.forename: Vishnu
authors.initials: V
authors.lastname: Ramani
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wessner
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martinez
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: John M
authors.initials: JM
authors.lastname: Chirgwin
authors.forename: Dana
authors.initials: D
authors.lastname: Gaddy
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000473:pathology*; D020033:Protein Isoforms; D053245:RANK Ligand; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse