Background: Interleukin (IL)-11, a cytokine produced by breast cancer, has been implicated in breast\r\ncancer-induced osteolysis (bone destruction) but the mechanism(s) of action remain controversial. Some studies\r\nshow that IL-11 is able to promote osteoclast formation independent of the receptor activator of NF-?B ligand\r\n(RANKL), while others demonstrate IL-11 can induce osteoclast formation by inducing osteoblasts to secrete RANKL.\r\nThis work aims to further investigate the role of IL-11 in metastasis-induced osteolysis by addressing a new\r\nhypothesis that IL-11 exerts effects on osteoclast progenitor cells.\r\nMethods: To address the precise role of breast cancer-derived IL-11 in osteoclastogenesis, we determined the\r\neffect of breast cancer conditioned media on osteoclast progenitor cells with or without an IL-11 neutralizing\r\nantibody. We next investigated whether recombinant IL-11 exerts effects on osteoclast progenitor cells and survival\r\nof mature osteoclasts. Finally, we examined the ability of IL-11 to mediate osteoclast formation in tissue culture\r\ndishes and on bone slices in the absence of RANKL, with suboptimal levels of RANKL, or from RANKL-pretreated\r\nmurine bone marrow macrophages (BMMs).\r\nResults: We found that freshly isolated murine bone marrow cells cultured in the presence of breast cancer\r\nconditioned media for 6 days gave rise to a population of cells which were able to form osteoclasts upon\r\ntreatment with RANKL and M-CSF. Moreover, a neutralizing anti-IL-11 antibody significantly inhibited the ability of\r\nbreast cancer conditioned media to promote the development and/or survival of osteoclast progenitor cells.\r\nSimilarly, recombinant IL-11 was able to sustain a population of osteoclast progenitor cells. However, IL-11 was\r\nunable to exert any effect on osteoclast survival, induce osteoclastogenesis independent of RANKL, or promote\r\nosteoclastogenesis in suboptimal RANKL conditions.\r\nConclusions: Our data indicate that a) IL-11 plays an important role in osteoclastogenesis by stimulating the\r\ndevelopment and/or survival of osteoclast progenitor cells and b) breast cancer may promote osteolysis in part by\r\nincreasing the pool of osteoclast progenitor cells via tumor cell-derived IL-11. However, given the heterogeneous\r\nnature of the bone marrow cells, the precise mechanism by which IL-11 treatment gives rise to a population of\r\nosteoclast progenitor cells warrants further investigation
Loading....