Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-κB ligand pathway

Manali S. Bendre, Aaron G. Margulies, Brandon Walser, Nisreen S. Akel, Sudeepa Bhattacharrya, Robert A. Skinner, Frances Swain, Vishnu Ramani, Khalid S. Mohammad, Lisa L. Wessner, Alfredo Martinez, Theresa A. Guise, John M. Chirgwin, Dana Gaddy, Larry J. Suva

Research output: Contribution to journalArticlepeer-review

187 Scopus citations


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-κB (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.

Original languageEnglish (US)
Pages (from-to)11001-11009
Number of pages9
JournalCancer Research
Issue number23
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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