The roles of osteoprotegerin in cancer, far beyond a bone player

Abstract

Osteoprotegerin (OPG), also known as tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), is a member of the tumor necrosis factor (TNF) receptor superfamily. Characterized by its ability to bind to receptor activator of nuclear factor kappa B ligand (RANKL), OPG is critically involved in bone remodeling. Emerging evidence implies that OPG is far beyond a bone-specific modulator, and is involved in multiple physiological and pathological processes, such as immunoregulation, vascular function, and fibrosis. Notably, numerous preclinical and clinical studies have been conducted to assess the participation of OPG in tumorigenesis and cancer development. Mechanistic studies have demonstrated that OPG is involved in multiple hallmarks of cancer, including tumor survival, epithelial to mesenchymal transition (EMT), neo-angiogenesis, invasion, and metastasis. In this review, we systematically summarize the basis and advances of OPG from its molecular structure to translational applications. In addition to its role in bone homeostasis, the physiological and pathological impacts of OPG on human health and its function in cancer progression are reviewed, providing a comprehensive understanding of OPG. We aim to draw more attention to OPG in the field of cancer, and to propose it as a promising diagnostic or prognostic biomarker as well as potential therapeutic target for cancer.

Fig. 1. Molecular structure and maturation process of secreted OPG.

The signaling peptide is removed from full length OPG molecule before being secreted. The secreted OPG is a homodimer linked by disulfide bonds. AA, amino acid, D (1–7) domain (1–7).

Fig. 2. OPG-related signaling pathways.

OPG is secreted in a homodimeric form. By binding with RANKL and TRAIL, OPG exerts its inhibitory effects on their downstream signaling pathways. Besides, OPG itself is regulated by many signaling pathway. Imbalanced signaling cross-talks between PI3K/AKT, p38/MAPK, wnt/β-catenin, TGF-β, mTOR and OPG contribute to the pathological cell behaviors. Other ligands, such as E2, vWF, FVIII-vWF and glycosaminoglycans (GAGs), bind with secreted OPG to impede its function. DR death receptor.

Fig. 3. Summary of the role of OPG in benign and malignant diseases.

OPG is involved in various physiological and pathological steps for disease progression, including bone remodeling, vascular calcification, angiogenesis, immunoregulation, fibrosis, cell survival and apoptosis, EMT, and cancer metastasis.