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 hematopoietic osteoclast precursor cells that leads to osteoclast ogenesis. Led first by the discovery of osteoprotegerin (OPG), a naturally occurring protein with potent osteoclastog(e)nesis inhibitory activity, rap id progress was made to the isolation of RANKL, a transmembrane ligand expr essed on osteoblasts/stromal cells that binds to RANK, a transmembrane rece ptor on hematopoietic osteoclast precursor cells. The interaction of RANK a nd RANKL initiates a signaling and gene expression cascade that results in differentiation and maturation of osteoclast precursor cells to active oste oclasts capable of resorbing bone. OPG acts as a decoy receptor, binding to RANKL. and blocking its interaction with RANK, inhibiting osteoblast devel opment. Many of the calciotropic hormones and cytokines, including 1,25(OH) (2)D-3, PTH, PGE(2) and IL-11, appear to act through a dual capacity to inh ibit production of OPG and stimulate production of RANKL. Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated ost eoclastogenesis. Recently, the results of the first clinical trial with OPG supported its potential as a therapeutic agent for diseases such as osteop orosis. The new understanding provided by the RANK/RANKL/OPG paradigm for b oth differentiation of osteoclasts and their activation has had tremendous impact on the field and opened new avenues for development of possible trea tments of diseases characterized by excessive bone resorption.