Journal Article

RANKL/RANK—beyond bones

Hanada, Reiko, Hanada, Toshikatsu, Penninger, Josef M., Sigl, Verena, Schramek, Daniel

2011

Overview

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-PGE 2 /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.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Animals / Astrocytes / Basal bodies / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Body temperature / Bone and Bones - metabolism / Bone cancer / Bone remodelling / Breast cancer / Central nervous system / Fever / General aspects / Human Genetics / Humans / Immune System - immunology / Immune System - metabolism / Internal Medicine / Lactation - metabolism / Mammary gland / Medical sciences / Metastases / Microenvironments / Molecular Medicine / Neoplasms - metabolism / NF- Kappa B protein / Pregnancy / RANK Ligand - immunology / RANK Ligand - metabolism / Receptor Activator of Nuclear Factor-kappa B - immunology / Receptor Activator of Nuclear Factor-kappa B - metabolism / Review / Sex hormones / Signal transduction / Signal Transduction - physiology / Thermoregulation / Thymus / TRANCE protein / Tumor necrosis factor