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. Key words: 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.Martin TJ. Historically significant events in the discovery of RANK/RANKL/OPG. World

Histochemical examination of the effects of high-dose 1,25(OH)2D3 on bone remodeling in young growing rats

“…The effects of vitamin D on osteoclastic activity has largely been established to be mediated via 1,25(OH) 2 D 3 activity on osteoblasts, which regulates the secretion of the key osteoclastogenesis factor, RANKL. RANKL/OPG ratio is an index of osteoclastogenic stimulation (Tanaka et al 2011) and plays a key role in the regulation of bone metabolism (Martin 2013). In this study, we found that high-dose 1,25(OH) 2 D 3 obviously increased the expression of RANKL and decreased the expression of OPG.…”

Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

“…7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs.…”

Increased receptor activator of nuclear factor κβ ligand/osteoprotegerin ratio exacerbates cartilage destruction in osteoarthritis in vitro

“…As members of the tumor necrosis factor superfamily, the molecular triad of osteoprotegerin (OPG)/receptor activator of nuclear factor κβ (RANK)/receptor activator of nuclear factor κβ ligand (RANKL) represents a key cytokine system for regulating bone metabolism (7,8). In OA, remodeling of the subchondral bone is reported to be RANKL-dependent, and osteoblasts express RANKL in subchondral bone (4,9).…”