Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Sep 30;59(10):1752.
doi: 10.3390/medicina59101752.

The RANK-RANKL-OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer

Diego De Leon-Oliva  1   2 , Silvestra Barrena-Blázquez  1   2   3 , Laura Jiménez-Álvarez  1   4 , Oscar Fraile-Martinez  1   2 , Cielo García-Montero  1   2 , Laura López-González  5 , Diego Torres-Carranza  1 , Luis M García-Puente  1   2 , Sara T Carranza  1   2 , Miguel Ángel Álvarez-Mon  1   2 , Melchor Álvarez-Mon  1   2   5   6 , Raul Diaz  2   4   5 , Miguel A Ortega  1   2
Affiliations
Review

The RANK-RANKL-OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer

Diego De Leon-Oliva et al. Medicina (Kaunas). .

Abstract

The RANK-RANKL-OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL is a ligand that binds to RANK, a receptor expressed on osteoclasts, dendritic cells, T cells, and other cells. RANKL signaling promotes osteoclast differentiation and activation, which leads to bone resorption. OPG is a decoy receptor that binds to RANKL and inhibits its signaling. In cancer cells, RANKL expression is often increased, which can lead to increased bone resorption and the development of bone metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown to be effective in the treatment of skeletal-related events, including osteoporosis or bone metastases, and cancer. This review will provide a comprehensive overview of the functions of the RANK-RANKL-OPG system in bone metabolism, mammary epithelial cells, immune function, and cancer, together with the potential therapeutic implications of the RANK-RANKL pathway for cancer management.

Keywords: RANK; RANKL; bone metastasis; breast cancer; immune system; osteoclast.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Bone remodeling. Osteoblasts express soluble and membrane-bound RANKL which binds to RANK in the membrane of osteoclast precursors. RANK signaling activates the differentiation towards osteoclasts. RANK signaling in osteoclasts promotes their bone resorptive activity and survival. Osteoblasts infiltrate into the cavities and synthesize the bone matrix. OPG is a decoy receptor produced by osteoblasts that binds RANKL, inhibiting the RANK signaling and regulating bone remodeling.
Figure 2
Figure 2
Development of lactating mammary glands. During pregnancy, progesterone binds to its cytoplasmic receptor, upregulating the expression of RANKL in luminal epithelial cells. RANKL binds to RANK in the neighboring cells, either luminal, basal or mammary stem cells, in a paracrine fashion. RANK signaling activates cell proliferation.
See this image and copyright information in PMC

References

    1. Lacey D.L., Timms E., Tan H., Kelley M.J., Dunstan C.R., Burgess T., Elliott R., Colombero A., Scully G.E.S., Hsu H., et al. Osteoprotegerin Ligand Is a Cytokine That Regulates Osteoclast Differentiation and Activation. Cell. 1998;93:165–176. doi: 10.1016/S0092-8674(00)81569-X. - DOI - PubMed
    1. Yasuda H., Shima N., Nakagawa N., Yamaguchi K., Kinosaki M., Mochizuki S.-I., Tomoyasu A., Yano K., Goto M., Murakami A., et al. Osteoclast Differentiation Factor Is a Ligand for Osteoprotegerin/Osteoclastogenesis-Inhibitory Factor and Is Identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA. 1998;95:3597–3602. doi: 10.1073/pnas.95.7.3597. - DOI - PMC - PubMed
    1. Li B., Wang P., Jiao J., Wei H., Xu W., Zhou P. Roles of the RANKL–RANK Axis in Immunity—Implications for Pathogenesis and Treatment of Bone Metastasis. Front. Immunol. 2022;13:824117. doi: 10.3389/fimmu.2022.824117. - DOI - PMC - PubMed
    1. Rao S., Cronin S.J.F., Sigl V., Penninger J.M. RANKL and RANK: From Mammalian Physiology to Cancer Treatment. Trends Cell Biol. 2018;28:213–223. doi: 10.1016/j.tcb.2017.11.001. - DOI - PubMed
    1. Akiyama T., Shimo Y., Yanai H., Qin J., Ohshima D., Maruyama Y., Asaumi Y., Kitazawa J., Takayanagi H., Penninger J.M., et al. The Tumor Necrosis Factor Family Receptors RANK and CD40 Cooperatively Establish the Thymic Medullary Microenvironment and Self-Tolerance. Immunity. 2008;29:423–437. doi: 10.1016/j.immuni.2008.06.015. - DOI - PubMed

Substances