Pathophysiology of RANK ligand (RANKL) and osteoprotegerin (OPG).

Receptor activator of nuclear factorκ B ligand (RANKL) is a membrane-bound peptide of the tumor necrosis factor (TNF) ligand superfamily [14]. Rich sources of RANKL expression include T lymphocytes [12] and osteoblastic lineage cells [8]. In the presence of permissive concentrations of macrophage-colony stimulating factor (M-CSF), RANKL stimulates the differentiation, proliferation, fusion and activation of osteoclastic lineage cells, resulting in an increased number of active osteoclasts and enhanced bone resorption [14, 22]. RANKL exerts its biological effects upon activating receptor activator of nuclear factor (NF)κ B (RANK), a transmembrane receptor of the TNF receptor (TNFR) superfamily which is mainly expressed by osteoclasts and dendritic cells [11]. Osteoprotegerin (OPG) represents a soluble receptor which belongs to the TNF receptor superfamily and acts as a receptor antagonist for RANKL [21]. OPG is ubiquitously produced by a variety of tissues, cell types, and cell lines, including mesenchymal stromal cells and osteoblasts. OPG binds both the soluble and cell-bound form of RANKL and, thus, prevents their interaction with, and stimulation, of RANK [14, 21]. Consistent with this, the in vitro effects of OPG include inhibition of osteoclast differentiation, survival, fusion, and activation of osteoclasts as well as stimulation of osteoclast apoptosis, thereby reducing the pool of active osteoclasts capable of resorbing bone [21]. Over the past years, it has become clear that RANKL and OPG are essential determinants of osteoclast cell biology and bone resorption [9, 22].