 RANKRANKL triggers a network of TRAF-mediated kinase cascades that promote osteoclast differentiation. RANKL is expressed on osteoblast cells and its receptor, Rank, on pre- osteoclastic cells. RANKL expression is stimulated by a number of factors, such as IL-1 , IL-6, IL-11 , IL-17, TNF- α, vitamin D, Ca2, parathyroid, glucocorticoids, prostaglandin E2, and immunosuppressive drugs, and is down-regulated by TGF-α. The RANKRANKL interaction induces differentiation and formation of multinucleated mature osteoclasts, causing bone resorption. The third protein agonist, osteoprotegerin OPG, is also produced by osteoblasts and is known to exert an inhibitory effect on the pre-osteoclastic differentiation process. By binding to RANKL also known as osteoprotegerin binding protein OPGbp, OPG inhibits the RANKRANKL interaction and subsequent osteoclastogenesis. OPG is thus a very efficient anti-resorptive agent. It also serves as a decoy receptor for the tumour necrosis factor-related apoptosis-inducing ligand TRAIL and increases cell survival by blocking the apoptotic effects of this ligand. The fact that the overexpression of OPG in mice results in severe osteopetrosis and that OPG-null mice are osteoporotic is testimony to the physiological importance of OPG. The lack of RANK or RANKL induces osteopetrosis in mice. 