Osteoprotegerin and its ligand: A new paradigm for regulation of osteoclastogenesis and bone resorption

In just 3 years, striking new advances have been made in understanding the molecular mechanisms that govern the crosstalk between osteoblasts/stromal cells and hemopoietic osteoclast precursor cells that leads to osteoclastog enesis. Led first by the discovery of osteoprotegerin (OPG), a naturally oc curring protein with potent osteoclastogenesis inhibitory activity, rapid p rogress was made to the isolation of RANKL, a transmembrane ligand expresse d on osteoblasts/stromal cells, that binds to RANK, a transmembrane recepto r on hemopoietic osteoclast precursor cells. The interaction of RANK and RA NKL initiates a signaling and gene expression cascade that results in diffe rentiation and maturation of osteoclast precursor cells to active osteoclas ts capable of resorbing bone. Osteoprotegerin acts as a decoy receptor; it binds to RANKL and blocks its interaction with RANK, thus inhibiting osteoc last development. Many of the calciotropic hormones and cytokines, includin g vitamin D3, parathyroid hormone, prostaglandin E2, and interleukin-ll, ap pear to stimulate osteoclastogenesis through the dual action of inhibiting production of OPG and stimulating production of RANKL. Estrogen, on the oth er hand, appears to inhibit production of RANKL and RANKL-stimulated osteoc lastogenesis. Recently, the results of the first clinical trial with OPG su pported its potential as a therapeutic agent for osteoporosis. The new unde rstanding provided by the RANK/RANKL/OPG paradigm for both differentiation and activation of osteoclasts has had tremendous impact on the field of bon e biology and has opened new avenues for development of possible treatments of diseases characterized by excessive bone resorption.