1. Academic Validation
  2. IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis

IL-11 is essential in promoting osteolysis in breast cancer bone metastasis via RANKL-independent activation of osteoclastogenesis

  • Cell Death Dis. 2019 Apr 30;10(5):353. doi: 10.1038/s41419-019-1594-1.
Mengmeng Liang 1 Qinyu Ma 2 Ning Ding 3 Fei Luo 2 Yun Bai 2 Fei Kang 1 Xiaoshan Gong 1 Rui Dong 1 Jingjin Dai 1 Qijie Dai 2 Ce Dou 4 Shiwu Dong 5 6 7
Affiliations

Affiliations

  • 1 Department of Biomedical Materials Science, Third Military Medical University, Chongqing, 400038, China.
  • 2 Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
  • 3 Department of promoting osteolysisBlood Purification, General Hospital of Shenyang Military Area Command, Shenyang, 110000, China.
  • 4 Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. [email protected].
  • 5 Department of Biomedical Materials Science, Third Military Medical University, Chongqing, 400038, China. [email protected].
  • 6 Department of Orthopedics, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. [email protected].
  • 7 State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400038, China. [email protected].
Abstract

A variety of osteolytic factors have been identified from breast Cancer cells leading to osteolysis, but less is known about which factor plays an essential role in the initiation process prior to the overt vicious osteolytic cycle. Here, we present in vitro and in vivo evidences to clarify the role of interleukin-11 (IL-11) as an essential contributor to breast Cancer bone metastasis mediated osteolysis. Animal studies showed that bone specific metastatic BoM-1833 cells induce earlier onset of osteolysis and faster tumor growth compared with MCF7 and parental MDA-MB-231 cells in BALB/c-nu/nu nude mice. IL-11 was further screened and identified as the indispensable factor secreted by BoM-1833 cells inducing osteoclastogenesis independently of receptor activator of nuclear factor κB ligand (RANKL). Mechanistic investigation revealed that the JAK1/STAT3 signaling pathway as a downstream effector of IL-11, STAT3 activation further induces the expression of c-Myc, a necessary factor required for osteoclastogenesis. By inhibiting STAT3 phosphorylation, AG-490 was shown effective in reducing osteolysis and tumor growth in the metastatic niche. Overall, our results revealed the essential role and the underlying molecular mechanism of IL-11 in breast Cancer bone metastasis mediated osteolysis. STAT3 targeting through AG-490 is a potential therapeutic strategy for mitigating osteolysis and tumor growth of bone metastatic breast Cancer.

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