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Brief Definitive Reports

Karen Fuller^*, Brian Wong, Simon Fox^*, Yongwon Choi^,, and Tim J. Chambers^*

From the ^* St. George's Hospital Medical School, London SW17 ORE, United Kingdom; and the Howard Hughes Medical Institute, The Rockefeller University, New York 10021

TRANCE (tumor necrosis factor–related activation-induced cytokine) is a recently described member of the tumor necrosis factor superfamily that stimulates dendritic cell survival and has also been found to induce osteoclastic differentiation from hemopoietic precursors. However, its effects on mature osteoclasts have not been defined. It has long been recognized that stimulation of osteoclasts by agents such as parathyroid hormone (PTH) occurs through a hormonal interaction with osteoblastic cells, which are thereby induced to activate osteoclasts. To determine whether TRANCE accounts for this activity, we tested its effects on mature osteoclasts. TRANCE rapidly induced a dramatic change in osteoclast motility and spreading and inhibited apoptosis. In populations of osteoclasts that were unresponsive to PTH, TRANCE caused activation of bone resorption equivalent to that induced by PTH in the presence of osteoblastic cells. Moreover, osteoblast-mediated stimulation of bone resorption was abrogated by soluble TRANCE receptor and by the soluble decoy receptor osteoprotegerin (OPG), and stimulation of isolated osteoclasts by TRANCE was neutralized by OPG. Thus, TRANCE expression by osteoblasts appears to be both necessary and sufficient for hormone-mediated activation of mature osteoclasts, and TRANCE-R is likely to be a receptor for signal transduction for activation of the osteoclast and its survival.

Key Words: osteoblast • osteoclast • TRANCE • bone resorption • parathyroid hormone

This work was in part supported by National Institutes of Health (NIH) MSTP grant GM-07739 (to B.R. Wong). Y. Choi is an investigator of the Howard Hughes Medical Institute.

Yongwon Choi and Tim J. Chambers share senior authorship.

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