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Trail down‐regulates the release of osteoprotegerin (OPG) by primary stromal cells
Author(s) -
Corallini Federica,
Celeghini Claudio,
Rimondi Erika,
di Iasio Maria Grazia,
Gonelli Arianna,
Secchiero Paola,
Zauli Giorgio
Publication year - 2011
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22564
Subject(s) - osteoprotegerin , rankl , stromal cell , mesenchymal stem cell , chemistry , microbiology and biotechnology , tumor necrosis factor alpha , p38 mitogen activated protein kinases , mapk/erk pathway , receptor , medicine , endocrinology , cancer research , phosphorylation , biology , activator (genetics) , biochemistry
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 ${\rm TNF} \hbox{-} {\tilde {\alpha }}$ 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. J. Cell. Physiol. 226: 2279–2286, 2011. © 2010 Wiley‐Liss, Inc.