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

BMC Cancer (Impact Factor: 3.36). 01/2013; 13(1):16. DOI: 10.1186/1471-2407-13-16
Source: PubMed


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.

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    • "Both IL-6 receptor (IL-6R) and IL- 11R have been identified in mature osteoclasts [23] [24]. IL-11 appears to have no direct effect on osteoclast activity or survival [25], and while IL-6 treatment of mature bone marrow-derived osteoclasts increased resorption of dentine, an effect that was blocked by an IL-6R neutralizing antibody [23], this data was not corrected for the number of osteoclasts present, and was not reproduced by others using similar systems [26] [27]. Although it is generally accepted that the major osteoclastogenic influence of IL-6 is mediated by RANKL production by osteoblast lineage cells [10- 12, 20] there are in vitro circumstances in which IL-6 directly stimulates osteoclast precursors to form osteoclasts [28] [29] or may partially facilitate RANKL or TNFαinduced osteoclastogenesis [26], and other conditions where IL-6 inhibits RANKLinduced osteoclastogenesis [30]. "
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    • "Zhao and coworkers showed that the receptor activator of nuclear factor κB ligand (RANKL), which was secreted by live osteocytes, promotes osteoclastogenesis [18]. Moreover, osteoprotegerin (OPG), as a soluble decoy receptor for RANKL, is also a crucial regulator of osteoclastogenesis [14, 19–22]. OPG can block osteoclastogenesis and maintain normal bone mass by binding RANKL and blocking interaction with RANK. "
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