Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family, is a dendritic cell survival factor and is essen tial for osteoclastogenesis and osteoclast activation. In this report we de monstrate (i) that TRANCE, like TNF-a, is made as a membrane-anchored precu rsor, which is released from the plasma membrane by a metalloprotease; (ii) that soluble TRANCE has potent dendritic cell survival and osteoclastogeni c activity; (iii) that the metalloprotease-disintegrin TNF-alpha convertase (TACE) can cleave immunoprecipitated TRANCE in vitro in a fashion that mim ics the cleavage observed in tissue culture cells; and (iv) that in vitro c leavage of a TRANCE ectodomain/CD8 fusion protein and of a peptide correspo nding to the TRANCE cleavage site by TACE occurs at the same site that is u sed when TRANCE is shed from cells into the supernatant. We propose that th e TRANCE ectodomain is released from cells by TACE or a related metalloprot ease-disintegrin, and that this release is an important component of the fu nction of TRANCE in bone and immune homeostasis.