Functions of RANKL/RANK/OPG in bone modeling and remodeling

Abstract

The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-kappaB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/OPG system in bone modeling and remodeling.

Figure. Signaling pathways involved osteoclastogenesis in disease states leading to activation of NFATc1

In inflammatory conditions, such as rheumatoid arthritis, the numbers of immune and accessory cells are increased in affected joints. Some of these cells produce RANKL in response to locally elevated levels of pro-inflammatory cytokines and other inflammatory mediators. RANKL binds to RANK on the surface of osteoclast precursors and recruits the adapter protein, TRAP6, leading to activation of NF-κB through phosphorylation and inactivation of inhibitory kappa kinases (IKKs) and NF-κB inhibitory kinase (not shown here). This induces activation of c-Fos. NF-κB and c-Fos interact with the NFATc1 promoter to trigger NFATc1 auto-amplification of NFATc1 and the transcription of genes, which mediate completion of the differentiation process. In addition to RANKL expression, these cells as well as macrophage/monocytes and osteoclasts themselves produce large amounts of TNF. TNF binds to the TNF receptor and this also activates c-Fos through both the NF-κB and JNK pathways in osteoclast precursors. TNF also stimulates its own expression and that of IL-1 by OCPs (orange lines). IL-1 does not activate c-Fos, but in OCPs in which c-Fos has been activated, for example by RANKL or TNF, IL-1 can induce osteoclastogenesis directly. This leads to more osteoclast formation using the same NFATc1 activated mechanism as RANKL. In this model, RANKL/RANK signaling is essential for OCP differentiation under both physiologic (through osteoblastic cells) and pathologic conditions (through accessory cells and OCP themselves), while TNF signaling appears to play a major role in inflammatory bone diseases.