TY - JOUR T1 - Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells. JF - J Cell Physiol Y1 - 2011 A1 - Corallini, Federica A1 - Celeghini, Claudio A1 - Rimondi, Erika A1 - di Iasio, Maria Grazia A1 - Gonelli, Arianna A1 - Secchiero, Paola A1 - Zauli, Giorgio KW - Bone Marrow Cells KW - Cell Death KW - Cells, Cultured KW - Coculture Techniques KW - Down-Regulation KW - Endothelial Cells KW - Enzyme Activation KW - Enzyme-Linked Immunosorbent Assay KW - Fibroblasts KW - Humans KW - MAP Kinase Signaling System KW - Mesenchymal Stromal Cells KW - Osteoprotegerin KW - p38 Mitogen-Activated Protein Kinases KW - Protein Binding KW - Recombinant Proteins KW - Stromal Cells KW - TNF-Related Apoptosis-Inducing Ligand KW - Tumor Necrosis Factor-alpha AB -
The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co-cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down-regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580.
VL - 226 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21660951?dopt=Abstract ER -