Biology of the RANKL–RANK–OPG System in Immunity, Bone, and Beyond

Abstract

Discovery and characterization of the cytokine receptor-cytokine-decoy receptor triad formed by receptor activator of nuclear factor kappa-B ligand (RANKL)–receptor activator of NF-κB (RANK)–osteoprotegerin (OPG) have led not only to immense advances in understanding the biology of bone homeostasis, but have also crystalized appreciation of the critical regulatory relationship that exists between bone and immunity, resulting in the emergence of the burgeoning field of osteoimmunology. RANKL–RANK–OPG are members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, and share signaling characteristics common to many members of each. Developmentally regulated and cell-type specific expression patterns of each of these factors have revealed key regulatory functions for RANKL–RANK–OPG in bone homeostasis, organogenesis, immune tolerance, and cancer. Successful efforts at designing and developing therapeutic agents targeting RANKL–RANK–OPG have been undertaken for osteoporosis, and additional efforts are underway for other conditions. In this review, we will summarize the basic biology of the RANKL–RANK–OPG system, relate its cell-type specific functions to system-wide mechanisms of development and homeostasis, and highlight emerging areas of interest for this cytokine group.

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…Furthermore, the survival of dendritic cells is up-modulated in the presence of RANKL [24]. These observations led to the development of a concept in which bone and immune tissues were functionally interconnected and it is at the origin of the "osteoimmunology" [25,26]. The RANKL/RANK/OPG system is associated to the pathogenesis of osteosarcoma [27][28][29], directly through RANK on the osteosarcoma cell surface [30] and indirectly by regulating osteoclast activities [31] and the tumor vascularization [32].…”

The effects of chitosan oligosaccharides on OPG and RANKL expression in a rat osteoarthritis model

“…By binding to RANKL, OPG inhibits the interaction of RANKL-RANK, thereby preventing RANK activation and subsequent osteoclastogenesis 13 . This system has also been reported to play roles in several cellular functions, which include apoptotic effect, immune response maintainance, and carcinogenesis 14,15 . Recently, studies showed that human OA chondrocytes also express and produce OPG, RANKL and RANK, and the molecular triad appears to be involved in OA progression 16 .…”

TLR5, a novel mediator of innate immunity‐induced osteoclastogenesis and bone loss

“…M-CSF is important for proliferation and survival of the progenitor cells. Crucial for osteoclastogenesis is activation of receptor activator of NF-kB (RANK) expressed on osteoclast progenitors by receptor activator of NF-kB ligand (RANKL), an interaction that is inhibited by the decoy receptor osteoprotegerin (OPG) (1). The balance between pro-and antiosteoclastogenic cytokines regulating RANKL:OPG expression is suggested to drive inflammation-induced osteoclastogenesis (2)(3)(4)(5).…”