Osteoprotegerin and osteoprotegerin ligand mediate the local regulation of bone resorption

Osteoblasts and marrow stromal cells are known to mediate the bone resorptive effects of osteotropic hormones and cytokines. The mechanism by which osteoblasts and stromal cells regulate osteoclastogenesis and osteoclast activation has been elusive, Recent discoveries have elucidated a signaling pathway that satisfies the requirements for this mediation. Osteoprotegerin ligand (OPGL), RANK, and osteoprotegerin (OPG) form a signal (agonist), receptor, and decoy receptor (antagonist) triad, OPG was discovered first as an inhibitor of osteoclastogenesis in vivo and in vitro. OPGL was identified by its binding affinity to OPG and is a potent stimulator of osteoclast differentiation, activation, and survival, in the absence of stromal cells. OPGL was found to be identical to TRANCE, which has been identified as a ligand for a tumor necrosis factor (TNF) receptor family member named RANK. RANK has been confirmed as the appropriate receptor for the effects of OPGL on bone resorption, Gene deletion studies in mice have shown that OPG is essential to maintain normal bone mass in mice and OPGL is essential for osteoclast formation, Osteotropic hormones and cytokines regulate OPG and OPGL expression in osteoblasts and marrow stromal cells to increase the OPGL signal for bone resorption.