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

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.

Prognosis value of circulating tumor cell PD‑L1 and baseline characteristics in patients with NSCLC treated with immune checkpoint inhibitors plus platinum‑containing drugs

“…In cancer cells, RANKL expression is frequently increased, leading to increased bone resorption and development of bone metastases. The specific role of the RANK-RANKL-OPG system in cancer development is thoroughly discussed by De Leon-Oliva et al ( 34 ). However, the relationship between these markers and treatment with ICIs plus platinum-containing drug treatment has not been reported.…”

Bone marrow adipocytes and lung cancer bone metastasis: unraveling the role of adipokines in the tumor microenvironment

“…3) Regulation of the activation and function of immune cells within the tumor microenvironment. In certain cases, activation of the RANKL/RANK signaling pathway induces immunosuppressive molecules (e.g., TGF-β from Treg cells), regulating the immune response balance, allowing lung cancer cells to evade immune surveillance and promote bone metastasis ( 67 ). Moreover, RANKL can stimulate the maturation and activation of dendritic cells, macrophages, and other immune cells, enhancing their cytokine and chemokine production, thus boosting antigen presentation and T cell activation capabilities ( 65 , 68 ).…”

Advanced Hydrogel-Based Strategies for Enhanced Bone and Cartilage Regeneration: A Comprehensive Review

“…Osteocytes are the most prevalent cells and are found in lacunae that are enclosed by a mineralized matrix, previously secreted as an osteoblast [32,33]. The osteoclasts are phagocytic multinucleated cells that have undergone terminal differentiation and are derived from the fusion of mononuclear cells of the hematopoietic stem cell (HSC) lineage under the effect of cytokines, such as receptor activator of nuclear factor κΒ ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) [34][35][36]. Finally, the bone lining cells are quiescent flat-shaped osteoblasts that protect the surfaces of bones where neither bone growth nor bone resorption takes place [37].…”