Journal of Molecular Medicine

, Volume 89, Issue 7, pp 647–656 | Cite as

RANKL/RANK—beyond bones

  • Reiko HanadaEmail author
  • Toshikatsu Hanada
  • Verena Sigl
  • Daniel Schramek
  • Josef M. Penninger


Receptor-activator of NF-κB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE, and ODF) and its tumor necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodeling, lymph node formation, establishment of the thymic microenvironment, mammary gland development during pregnancy, and bone metastasis in cancer. We have recently also reported that the RANKL/RANK system controls the incidence and onset of sex hormone, progestin-driven breast cancer. RANKL and RANK are also expressed in the central nervous systems where they play an essential role in body temperature regulation. RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE2/EP3R pathway. Moreover, female mice with a RANK gene deleted in neurons and astrocytes exhibit increased basal body temperature, suggesting that the RANKL/RANK system also controls physiological thermoregulation in females under the control of sex hormones. This review will summarize the recently emerging role of the RANKL/RANK signaling axis in mammary gland development, cancer metastasis, hormone-derived breast cancer development, and thermal regulation. Furthermore, we will highlight the striking therapeutic potential of this pathway and provide a molecular rationale for consideration of targeting RANKL/RANK in diseases such as breast cancer.


RANKL/RANK system Osteoclastogenesis Immunology Cancer Central nervous systems Fever 



This work is supported by grants from Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), the Austrian Ministry of Sciences, the Austrian Academy of Sciences, Genome Research in Austria (GEN-AU) (AustroMouse), an EU Marie Curie Excellence Grant, and an EU European Research Council (ERC) Advanced Grant. This work is also supported in part by Uehara Foundation and Japan Foundation for Applied Enzymology grants. We are grateful to Victor Navas, Magdalena Paolino, Vanja Nagy, Michael Orthofer, and Thomas Perlot for their helpful comments on this manuscript.

Conflict of interest



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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Reiko Hanada
    • 1
    Email author
  • Toshikatsu Hanada
    • 1
  • Verena Sigl
    • 1
  • Daniel Schramek
    • 1
  • Josef M. Penninger
    • 1
  1. 1.IMBA, Institute of Molecular Biotechnology of the Austrian Academy of SciencesViennaAustria

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