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Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond

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Abstract

More than 2 decades ago, the discovery of osteoprotegerin (OPG) as inhibitor of the receptor of activator of nuclear factor Kb (RANK) ligand (RANKL) revolutionized our understanding of bone biology and oncology. Besides acting as decoy receptor for RANKL, OPG acts as decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, RANKL, and TRAIL are ubiquitously expressed, stimulating per se pivotal signaling cascades implicated in cancer. In the context of cancer cell–bone cell interactions, cancer cells skew the OPG/RANKL/RANK (RANKL cognate receptor) balance towards bone destruction and tumor growth through favoring the RANKL/RANK interface, circumventing OPG. Numerous preclinical and clinical studies demonstrate the dual role of OPG in cancer: antitumor and tumor-promoting. OPG potentially conveys an antitumor signal through inhibiting the tumor-promoting RANKL signaling—both the osteoclast-dependent and the osteoclast-independent—and the tumor-promoting TRAIL signaling. On the other hand, the presumed tumor-promoting functions of OPG are: (i) abrogation of TRAIL-induced apoptosis of cancer cells; (ii) abrogation of RANKL-induced antitumor immunity; and (iii) stimulation of oncogenic and prometastatic signaling cascades downstream of the interaction of OPG with diverse proteins. The present review dissects the role of OPG in bone oncology. It presents the available preclinical and clinical data sustaining the dual role of OPG in cancer and focuses on the imbalanced RANKL/RANK/OPG interplay in the landmark “vicious cycle” of skeletal metastatic disease, osteosarcoma, and multiple myeloma. Finally, current challenges and future perspectives in exploiting OPG signaling in bone oncology therapeutics are discussed.

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  1. Clinical Pharmacology Unit, Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias Str, Goudi, 11527, Athens, Greece

    Maria V. Deligiorgi & Dimitrios T. Trafalis

  2. Department of Applied Sciences, Northumbria University, Ellison Building, Room A516, Newcastle upon Tyne, NE1 8ST, UK

    Mihalis I. Panayiotidis

  3. 1st Department of Surgery, Faculty of Medicine, National and Kapodistrian University of Athens, Laikon General Hospital, 17 Agiou Thoma Str, Goudi, 115-27, Athens, Greece

    John Griniatsos

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Deligiorgi, M.V., Panayiotidis, M.I., Griniatsos, J. et al. Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond. Clin Exp Metastasis 37, 13–30 (2020). https://doi.org/10.1007/s10585-019-09997-8

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