Biology of RANK, RANKL, and osteoprotegerin

Abstract

The discovery of the receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.

Figure 1

The essential signaling pathway for normal osteoclastogenesis. Under physiologic conditions, RANKL produced by osteoblasts binds to RANK on the surface of osteoclast precursors and recruits the adaptor protein TRAF6, leading to NF-κB activation and translocation to the nucleus. NF-κB increases c-Fos expression and c-Fos interacts with NFATc1 to trigger the transcription of osteoclastogenic genes. OPG inhibits the initiation of the process by binding to RANKL. NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand; TRAF, tumor necrosis factor receptor associated factor.

Figure 2

Osteoclasts and precursors are secretory cells. In inflammatory bone disease, systemic elevated TNF stimulates the generation of OCPs in the bone marrow and also enhances their egress into the bloodstream, from where they can alight in increased numbers at sites of inflammation. These OCPs differentiate to osteoclasts and increase their production of many factors in response to TNF and RANKL and thereby induce an auto-amplifying autocrine vicious cycle to increase osteoclast numbers and interact with immune and other cells to affect bone volume and turnover. OCP, osteoclast precursor; RANKL, receptor activator of nuclear factor-κB ligand; TNF, tumor necrosis factor.

Figure 3

The role of the RANKL/RANK system in bone and other tissues. RANKL is produced by a variety of cell types and its expression is regulated by many physiologic and pathologic factors. Preclinical studies in mice and studies of human tissues have revealed functions for RANKL/RANK signaling in normal and pathologic states. OPG can bind to RANKL and prevent its interaction with RANK to inhibit osteoclast formation, but its effects on other cellular functions of RANKL have yet to be determined. OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand.