Abstract
The role of the receptor activator of nuclear factor-κB ligand (RANKL)/RANK system is well characterized within bone, where RANKL/RANK signaling mediates osteoclastogenesis and bone resorption. However, this system has also been shown to influence biologic processes beyond the skeletal system, including in the immune system and in cancer. RANKL/RANK signaling is important in lymph-node development, lymphocyte differentiation, dendritic cell survival, T-cell activation, and tolerance induction. The RANKL/RANK axis may also have direct, osteoclast-independent effects on tumor cells. Indeed, activity of the RANKL/RANK pathway in cancer cells has been correlated with tumor progression and advanced disease. Denosumab, a fully human monoclonal antibody against RANKL, inhibits osteoclastogenesis and is widely used not just for the treatment of osteoporosis, but for the prevention of skeletal-related events from bone metastases in solid malignancies such as breast and prostate cancer. The potential effects of denosumab on the immune system have been largely ignored. Nevertheless, with the emergence of immunotherapies for cancer, denosumab may impact the effectiveness of these therapies, especially if they are given in combination. In this article, we review the role of RANKL/RANK in bone, immunity, and cancer. Examining the potential effects of routine treatment with denosumab beyond the bone represents an important area of investigation.
Highlights
The skeletal architecture is maintained through a complex remodeling process mediated by osteoblasts, responsible for bone formation, and osteoclasts, responsible for bone resorption
Osteoblasts are derived from mesenchymal stem cells, and their differentiation is induced by several specific transcription factors, including core-binding factor α1 (Cbfa1) and osterix (Osx), as well as by the bone morphogenic proteins BMP-2, BMP-4, and BMP-7
RANKL is a member of the tumor necrosis factor (TNF) family, as is known as TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF)
Summary
The skeletal architecture is maintained through a complex remodeling process mediated by osteoblasts, responsible for bone formation, and osteoclasts, responsible for bone resorption. Osteoblasts are derived from mesenchymal stem cells, and their differentiation is induced by several specific transcription factors, including core-binding factor α1 (Cbfa1) and osterix (Osx), as well as by the bone morphogenic proteins BMP-2, BMP-4, and BMP-7. Osteoclastogenesis requires stimulation by macrophage-colony stimulating factor (M-CSF) and the binding of receptor activator of nuclear factorκB ligand (RANKL), expressed on osteoblasts, to RANK receptor on the osteoclast precursors. Osteoclasts are inhibited by multiple soluble factors, including OPG, an endogenous decoy receptor of RANKL secreted by osteoblasts and expressed in several other tissues, including lung, heart, and kidney. Tumor-derived factors including parathyroid hormonereleasing protein (PTHrP), prostaglandin E2 (PGE2), TNFα, and interleukins, have been demonstrated to enhance RANKL expression by osteoblasts and other bone stromal cells present, and diminish OPG expression [5]. RANKL is upregulated with T-cell receptor (TCR) stimulation, and may www.frontiersin.org
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
