title: IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells.
abstract: BACKGROUND
  Interleukin (IL)-11, a cytokine produced by breast cancer, has been implicated in breast cancer-induced osteolysis (bone destruction) but the mechanism(s) of action remain controversial. Some studies show that IL-11 is able to promote osteoclast formation independent of the receptor activator of NF-κB ligand (RANKL), while others demonstrate IL-11 can induce osteoclast formation by inducing osteoblasts to secrete RANKL. This work aims to further investigate the role of IL-11 in metastasis-induced osteolysis by addressing a new hypothesis that IL-11 exerts effects on osteoclast progenitor cells.
  
  
  METHODS
  To address the precise role of breast cancer-derived IL-11 in osteoclastogenesis, we determined the effect of breast cancer conditioned media on osteoclast progenitor cells with or without an IL-11 neutralizing antibody. We next investigated whether recombinant IL-11 exerts effects on osteoclast progenitor cells and survival of mature osteoclasts. Finally, we examined the ability of IL-11 to mediate osteoclast formation in tissue culture dishes and on bone slices in the absence of RANKL, with suboptimal levels of RANKL, or from RANKL-pretreated murine bone marrow macrophages (BMMs).
  
  
  RESULTS
  We found that freshly isolated murine bone marrow cells cultured in the presence of breast cancer conditioned media for 6 days gave rise to a population of cells which were able to form osteoclasts upon treatment with RANKL and M-CSF. Moreover, a neutralizing anti-IL-11 antibody significantly inhibited the ability of breast cancer conditioned media to promote the development and/or survival of osteoclast progenitor cells. Similarly, recombinant IL-11 was able to sustain a population of osteoclast progenitor cells. However, IL-11 was unable to exert any effect on osteoclast survival, induce osteoclastogenesis independent of RANKL, or promote osteoclastogenesis in suboptimal RANKL conditions.
  
  
  CONCLUSIONS
  Our data indicate that a) IL-11 plays an important role in osteoclastogenesis by stimulating the development and/or survival of osteoclast progenitor cells and b) breast cancer may promote osteolysis in part by increasing the pool of osteoclast progenitor cells via tumor cell-derived IL-11. However, given the heterogeneous nature of the bone marrow cells, the precise mechanism by which IL-11 treatment gives rise to a population of osteoclast progenitor cells warrants further investigation.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors: Erin M
authors: EM
authors: McCoy
authors: Huixian
authors: H
authors: Hong
authors: Hawley C
authors: HC
authors: Pruitt
authors: Xu
authors: X
authors: Feng
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000378:metabolism; D005260:Female; D006801:Humans; D017370:Interleukin-11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010014:Osteolysis / Q000276:immunology / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; C508611:IL11 protein, human; D017370:Interleukin-11; D053245:RANK Ligand; D011994:Recombinant Proteins; D016173:Macrophage Colony-Stimulating Factor