IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells

• Published in: BMC cancer Vol. 13; no. 1; p. 16
• Main Authors: McCoy, Erin M, Hong, Huixian, Pruitt, Hawley C, Feng, Xu
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 11.01.2013; BioMed Central; BMC
• Subjects: Animals; Antibodies; Antibodies, Neutralizing - pharmacology; B cells; Bone marrow; Bone metastasis; Bone resorption; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Cell Line, Tumor; Cell Survival; Culture Media, Conditioned - metabolism; Cytokines; Female; Humans; Interleukin-11; Interleukin-11 - antagonists & inhibitors; Interleukin-11 - metabolism; Interleukins; Ligands; Macrophage Colony-Stimulating Factor - metabolism; Macrophages - metabolism; Metastasis; Mice; Mice, Inbred C57BL; Osteoclast; Osteoclasts (Biology); Osteoclasts - drug effects; Osteoclasts - immunology; Osteoclasts - metabolism; Osteolysis; Osteolysis - immunology; Osteolysis - metabolism; Paracrine Communication - drug effects; Physiological aspects; RANK Ligand - metabolism; RANKL; Recombinant Proteins - metabolism; Stem Cells - drug effects; Stem Cells - immunology; Stem Cells - metabolism; Studies; Time Factors; Tumors; Viral antibodies
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/1471-2407-13-16

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. 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). 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. 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.