ABSTRACT
S keletal homeostasis is m aintained by a delicate balance between bone-resorbing osteoclasts and bone-building osteoblasts. Recendy, three novel tumor necrosis factor (TNF) ligand and receptor family members have been identified as critical extracellular regulators of bone resorption: osteoprotegerin (OPG), receptor activator of nuclear factor NF-kB ligand (RANKL) or osteoprotegerin ligand (OPGL), and receptor activator of NF-kB (RANK). The subsequent characterization of the OPG-RANKL-RANK signal transduction pathway has elucidated the molecular mechanisms of osteoclast dif ferentiation, activation, and survival, thus greatly expanded our basic understand ing o f osteoclast biology. In this new paradigm for the regulation of osteoclastogenesis and bone resorption, binding of RANKL to its transmembrane receptor RANK, expressed on the cell surface of hematopoietic osteoclast precur sors and mature osteoclasts, initiates a signaling cascade that eventually leads to the differentiation and activation of osteoclasts. OPG, acting as a soluble decoy receptor, can bind to RANKL and uncouple the interaction between osteoblasts/ stromal cells and osteoclast precursors, thereby inhibiting the osteoclast formation and maturation process. Both produced by osteoblasts and stromal cells, RANKL and OPG are regulated by various calciotropic hormones and pro-resorptive cytokines, and serve as the ultimate humoral mediator of bone resorption and calcium metabolism. In fact, it is the relative levels of RANKL and OPG expres sion that dictates the extent of bone resorption: excess RANKL increases bone resorption whereas excess OPG inhibit it. The biological importance of this path way is underscored by the induction of extreme skeletal phenotypes, severe os teoporosis and osteopetrosis, via molecular genetic manipulation of these three extracellular signaling components in mice, as well as the identification of various genetic mutations in this pathway that cause several forms of rare human
TNF Superfamily, edited by Sanjay Khare. © 2007 Landes Bioscience
genetic bone disorders. Perturbation of the OPG-RANKL-RANK signaling path way has been implicated in the pathogenesis of many metabolic bone diseases, such as postmenopausal osteoporosis, bone loss associated with rheumatoid ar thritis, tumor bone metastases, and humoral hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or inhibit these osteolytic events in animal models that mimic these human disorders. More importantly, prom ising results from the first series of human clinical studies with recombinant OPG have further highlighted the therapeutic potential of targeting this signaling pathway for the treatment of osteolytic bone diseases such as osteoporosis and tumor bone metastases.
