Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival

Abstract

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family, is a dendritic cell survival factor and is essential for osteoclastogenesis and osteoclast activation. In this report we demonstrate (i) that TRANCE, like TNF-␣, is made as a membrane-anchored precursor, which is released from the plasma membrane by a metalloprotease; (ii) that soluble TRANCE has potent dendritic cell survival and osteoclastogenic activity; (iii) that the metalloprotease-disintegrin TNF-␣ convertase (TACE) can cleave immunoprecipitated TRANCE in vitro in a fashion that mimics the cleavage observed in tissue culture cells; and (iv) that in vitro cleavage of a TRANCE ectodomain/CD8 fusion protein and of a peptide corresponding to the TRANCE cleavage site by TACE occurs at the same site that is used when TRANCE is shed from cells into the supernatant. We propose that the TRANCE ectodomain is released from cells by TACE or a related metalloprotease-disintegrin, and that this release is an important component of the function of TRANCE in bone and immune homeostasis. Tumor necrosis factor (TNF)1 -related activation-induced cytokine (TRANCE), a recently identified member of the TNF family, is a dendritic cell survival factor that also has a role in bone homeostasis (1-4). Like TNF-␣, TRANCE is a type II integral membrane glycoprotein of ϳ45 kDa with a long extracellular stalk region followed by a receptor-binding core domain (5). TRANCE expression in osteoblasts and stromal cells can be induced with vitamin D3, prostaglandin E 2 , interleukin-1, or glucocorticoids (4). In turn, TRANCE is known to induce differentiation and activation of osteoclasts. This suggests that TRANCE provides an important link between the action of hormones and physiological cytokines and bone resorption. TRANCE is also expressed on activated T cells (5), where it induces dendritic cell survival, thereby enhancing T cell priming (1, 2). Therefore TRANCE may also regulate antigen presentation during an immune response. TRANCE mediates its effects through the membrane-anchored TRANCE receptor (TRANCE-R, also referred to as RANK (receptor activator of nuclear factor-B)), which results in activation of c-Jun Nterminal kinase and nuclear factor-B (2, 5). Finally TRANCE is known to bind to a soluble receptor, termed osteoprotegerin or osteoclast inhibitory factor (OPG/OCIF), which is a member of the TNF-␣ receptor family (6). OPG/OCIF presumably functions as a decoy receptor, since systemic overexpression or injection of OPG/OCIF causes osteopetrosis in mice (7), whereas OPG/OCIF deficiency results in osteoporosis (8).Similar to TNF-␣, which is thought to be released from the plasma membrane by the metalloprotease-disintegrin TNF-␣ convertase (TACE) (9 -11), TRANCE may also be shed by TACE or a related metalloprotease. Metalloproteases have been implicated in the shedding or release of several different cell surface proteins from the plasma membrane. These proteins include various cytokines, cytokine receptors, adhesion proteins, and...

Molecular Variations Related to the Regional Differences in Periosteal Growth at the Mandibular Ramus

“…A molecular weight of $50 kD was unexpectedly higher than the predicted molecular weight for transmembrane RANKL (Wong et al, 1997), but similar findings have been reported before. Using the same antibody (Santa Cruz Biotech, CA), Dossing and Stern (2005) reported a band of $52 kD for RANKL, and the increased molecular weight has been attributed to RANKL glycosylation (Wong et al, 1997;Lum et al, 1999). These reports confirm that our identification of a $50-kD RANKL band by Western blot was specific and reliable.…”

Porphyromonas gingivalis Induces RANKL in T-cells

“…It is also interesting to note that Jurkat T-cells produce TACE in response to P. gingivalis challenge [26]. TACE is a metalloprotease able to shed RANKL from the cell membrane surface, thus facilitating its release into the immediate extracellular environment and propagating its action [27].…”

Enhanced metastatic dissemination to multiple organs by melanoma and lymphoma cells in timp-3−/− mice

“…Bone matrix contains a number of osteoblast-associated factors that not only stimulate proliferation of endogenous bone cells, but also of tumor cells (Orr et al, 1993). For instance, the release of membrane-bound RANKL by MT1-MMP and ADAM-17 enhances its availability for RANK-receptor and activation of osteoclasts (Lum et al, 1999). Higher MT1-MMP activity in timp-3 À/À tissue, as reflected by MMP-2 activation, could result in greater osteoclast activation and osteolysis.…”