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Mechanisms of Disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis

Nature Clinical Practice Oncology volume 3, pages 41–49 (2006)Cite this article

Abstract

The discovery of osteoprotegerin, receptor activator of nuclear factor kappa B (RANK) and RANK ligand as critical molecular determinants of osteoclastogenesis and regulators of bone resorption, has revolutionized our understanding of the processes of normal and pathological bone biology. Altering the relative biological availabilities of these molecules has direct consequences for the regulation of both bone resorption and bone remodeling. Importantly, recent research suggests a pivotal role for these molecules in mediating cancer-induced bone destruction. This review summarizes the current evidence of osteoprotegerin, RANK ligand and RANK involvement in the pathophysiology of skeletal metastasis, and of therapeutic targeting of this process.

Key Points

  • The equilibrium between bone resorption and new bone formation is disrupted in tumor cells, with most displaying osteolytic features

  • Patterns of OPG expression differ in primary tumors compared with metastatic lesions, even within the same patient, and could be promising markers of disease progression

  • The RANKL: OPG ratio is significantly increased in cancer patients and those with other osteolytic pathologies, which may be used as a prognostic indicator of osteolysis

  • Preclinical data indicate that targeting resorption via inhibition of RANKL activity might be effective in managing pain

  • RANKL-independent pathways important in normal bone remodeling could also play a role in the regulation of cancer-related bone lesions

  • Understanding the process of bone resorption will provide new insights into the mechanism of bone metastases, ultimately leading to new treatment and prevention strategies

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Figure 1: Radiographs of the femurs of 4–6-week-old mice that lack functional genes for OPG, RANKL or RANK
Figure 2: Model of the role of OPG and RANKL in cancer-bone interactions
Figure 3: Serum OPG levels in prostate cancer increase with disease progression
Figure 4: Administration of OPG-Fc inhibits the establishment and growth of lytic human prostate cancer lesions in the bones of immunocompromised mice

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Acknowledgements

We acknowledge those whose work was not directly cited because of space constraints. This work was supported in part by the Cure Cancer Australia Foundation, the Clive and Vera Ramaciotti Foundation, Amgen Inc., National Health and Medical Research Council grant No. 352322, the New South Wales Government Ministry for Science and Medical Research BioFirst Award and the University of Sydney Cancer Research Fund.

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Authors and Affiliations

  1. Bone Biology program at the ANZAC Research Institute,

    Julie M Blair, Hong Zhou, Markus J Seibel & Colin R Dunstan

  2. Bone Research Program at the ANZAC Research Institute,

    Julie M Blair, Hong Zhou, Markus J Seibel & Colin R Dunstan

  3. University of Sydney,

    Julie M Blair, Hong Zhou, Markus J Seibel & Colin R Dunstan

  4. ANZAC Research Institute, Sydney, Australia

    Julie M Blair, Hong Zhou, Markus J Seibel & Colin R Dunstan

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Correspondence to Julie M Blair.

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Competing interests

CR Dunstan is an owner of Amgen stock. Part funding was received from Amgen Inc for the study described in Figure 4.

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Blair, J., Zhou, H., Seibel, M. et al. Mechanisms of Disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nat Rev Clin Oncol 3, 41–49 (2006). https://doi.org/10.1038/ncponc0381

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