TRANCE IS NECESSARY AND SUFFICIENT FOR OSTEOBLAST-MEDIATED ACTIVATIONOF BONE-RESORPTION IN OSTEOCLASTS

TRANCE (tumor necrosis factor-related activation-induced cytokine) is a recently described member of the tumor necrosis factor superfamily t hat stimulates dendritic cell survival and has also been found to indu ce osteoclastic differentiation from hemopoietic precursors. However, its effects on mature osteoclasts have not been defined. It has long b een recognized that stimulation of osteoclasts by agents such as parat hyroid hormone (PTH) occurs through a hormonal interaction with osteob lastic cells, which are thereby induced to activate osteoclasts. To de termine whether TRANCE accounts for this activity, we tested its effec ts on mature osteoclasts. TRANCE rapidly induced a dramatic change in osteoclast motility and spreading and inhibited apoptosis. In populati ons of osteoclasts that were unresponsive to PTH, TRANCE caused activa tion of bone resorption equivalent to that induced by PTH in the prese nce of osteoblastic cells. Moreover, osteoblast-mediated stimulation o f bone resorption was abrogated by soluble TRANCE receptor and by the soluble decoy receptor osteoprotegerin (OPG), and stimulation of isola ted osteoclasts by TRANCE was neutralized by OPG. Thus, TRANCE express ion by osteoblasts appears to be both necessary and sufficient for hor mone-mediated activation of mature osteoclasts, and TRANCE-R is likely to be a receptor for signal transduction for activation of the osteoc last and its survival.