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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    ABSTRACT: Interleukin-6 (IL-6) and interleukin-11 (IL-11) receptors (IL-6R and IL-11R, respectively) are both expressed in osteoclasts and transduce signal via the glycoprotein130 (gp130) co-receptor, but the physiological role of this pathway is unclear. To determine the critical roles of gp130 signaling in the osteoclast, we generated mice using cathepsin K Cre (CtskCre) to disrupt gp130 signalling in osteoclasts. Bone marrow macrophages from CtskCre.gp130(f/f) mice generated more osteoclasts in vitro than cells from CtskCre.gp130(w/w) mice; these osteoclasts were also larger and had more nuclei than controls. While no increase in osteoclast numbers was observed in vivo, osteoclasts on trabecular bone surfaces of CtskCre.gp130(f/f) mice were more spread out than in control mice, but had no functional defect detectable by serum CTX1 levels or trabecular bone cartilage remnants. However, trabecular osteoblast number and mineralising surfaces were significantly lower in male CtskCre.gp130(f/f) mice compared to controls, and this was associated with a significantly lower trabecular bone volume at 12 weeks of age. Furthermore, CtskCre.gp130(f/f) mice exhibited greatly suppressed periosteal bone formation at this age, indicated by significant reductions in both double-labeled surface and mineral apposition rate. By 26 weeks, CtskCre.gp130(f/f) mice exhibited narrower femora, with lower periosteal and endocortical perimeters than CtskCre.gp130(w/w) controls. Since IL-6 and IL-11R global knockout mice exhibited a similar reduction in femoral width, we also assessed periosteal bone formation in those strains, and found bone forming surfaces were reduced to a similar extent in male IL-6 null mice. These data suggest that IL-6/gp130 signalling in the osteoclast is not essential for normal bone resorption in vivo, but maintains both trabecular and periosteal bone formation in male mice by promoting osteoblast activity. Copyright © 2015. Published by Elsevier Inc.
    Bone 08/2015; DOI:10.1016/j.bone.2015.08.005 · 3.97 Impact Factor
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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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    02/2014; 2014:284836. DOI:10.1155/2014/284836
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    Clinical and Experimental Metastasis 02/2014; 31(5). DOI:10.1007/s10585-014-9642-9 · 3.49 Impact Factor
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