RANKL biology

Abstract

Since the receptor activator of nuclear factor-kappa B ligand (RANKL), its cognate receptor activator of nuclear factor-kappa B (RANK), and the decoy receptor osteoprotegerin (OPG) were discovered, a number of studies have uncovered the crucial role of the RANKL-RANK-OPG pathway in controlling the key aspect of bone homeostasis, the immune system, inflammation, cancer, and other systems under pathophysiological condition. These findings have expanded the understanding of the multifunctional biology of the RANKL-RANK-OPG pathway and led to the development of therapeutic potential targeting this pathway. The successful development and application of anti-RANKL antibody in treating diseases causing bone loss validates the utility of therapeutic approaches based on the modulation of this pathway. Moreover, recent studies have demonstrated the involvement of the RANKL-RANK pathway in osteoblast differentiation and bone formation, shedding light on the RANKL-RANK dual signaling in coupling bone resorption and bone formation. In this review, we will summarize the current understanding of the RANKL-RANK-OPG system in the context of the bone and the immune system as well as the impact of this pathway in disease conditions, including cancer development and metastasis.

Figure 1

The RANKL-RANK-OPG pathway in osteoclast and osteoblast differentiation. RANKL is mainly produced by osteoblasts and osteocytes, while RANK is mainly expressed by cells of a hematopoietic origin, including osteoclasts and their precursors. The ligation of RANK by RANKL leads to the activation of downstream signaling pathway and promotes nuclear translocation and activation of NFATc1 and NF-kB, causing osteoclast differentiation. OPG and LGR4, both of which interact with RANKL, are endogenous inhibitors of the RANKL-RANK pathway. RANKL has also been reported to function as a receptor of RANK, serving reserve signaling. The ligation of RANKL by RANK activates RANKL reverse signaling through a proline-rich motif. The soluble form of RANKL (sRANKL) can be expressed by alternative splicing or produced through proteolytic cleavage by matrix metalloproteinases. sRANKL is functional to activate RANK signaling. The expression of RANK and LGR4 has been reported in osteoblastic lineage cells, and sRANKL might activate osteoblast differentiation through these receptors as an autocrine-paracrine loop.

Figure 2

RANKL regulates osteolytic bone metastasis through the stimulation of cancer cell migration toward the bone. RANKL acts directly on RANK-expressing tumor cells and promotes cell migration. Tumor cells induce RANKL expression on bone marrow stromal cells, leading to osteoclastic bone resorption. Increased bone resorption resulted in the release of factors that promote tumor growth (vicious cycle). Denosumab prevents osteoclastic bone destruction. Denosumab also has the potential to treat tumors in combination with immune checkpoint inhibitors.

Figure 3

RANKL–RANK binding increases osteoclast formation, activity, and survival. Human anti-RANKL monoclonal antibody denosumab has been clinically used for treatment of osteoporosis and prevention of skeletal-related events (SREs). Several studies have shown the potential therapeutic benefits of denosumab for osteoclastic bone loss such as rheumatoid arthritis.

Fig. 4.

RANKL–RANK binding increases osteoclast formation, activity, and survival. Human anti-RANKL monoclonal antibody denosumab has been clinically used for treatment of osteoporosis and prevention of skeletal-related events (SREs). Several studies have shown the potential therapeutic benefits of denosumab for osteoclastic bone loss such as rheumatoid arthritis.