Historically significant events in the discovery of RANK/RANKL/OPG

Abstract

After it was suggested 30 years ago that the osteoblast lineage controlled the formation of osteoclasts, methods were developed that established this to be the case, but the molecular controls were elusive. Over more than a decade much evidence was obtained for signaling mechanisms that regulated the production of a membrane - bound regulator of osteoclastogenesis, in the course of which intercellular communication in bone was revealed in its complexity. The discovery of regulation by tumor necrosis factor ligand and receptor families was made in the last few years of the twentieth century, leading since then to a new physiology of bone, and to exciting drug development.

Keywords: Receptor activator of nuclear factor κB ligand; Osteoprotegerin; Receptor activator of nuclear factor κB; Osteoclasts; Bone biology

Core tip: The history of discovery of receptor activator of nuclear factor κB ligand began with the hypothesis that the osteoblast lineage controls osteoclast formation. The hypothesis was confirmed by experiments showing first, that osteoblastic cells were necessary for osteoclast activation, then some years later that osteoblasts were necessary for osteoclast formation in a contact-dependent process. Ultimate confirmation came from mouse genetics, discovering inhibition of osteoblast formation by a secreted tumor necrosis factor (TNF) ligand, followed by discovery of promotion of osteoclast formation by a membrane-bound member of the TNF ligand family that signalled through its receptor in hemopoietic cells to promote osteoclast formation.