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Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels
Author(s) -
Kondo Takeshi,
Kitazawa Riko,
Yamaguchi Akira,
Kitazawa Sohei
Publication year - 2007
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21414
Subject(s) - osteoprotegerin , rankl , endocrinology , medicine , bone resorption , glucocorticoid , glucocorticoid receptor , activator (genetics) , osteoblast , chemistry , p38 mitogen activated protein kinases , mapk/erk pathway , protein kinase a , osteoclast , kinase , signal transduction , receptor , biology , in vitro , biochemistry
Increased bone fragility attributed to osteopenia is a serious side effect of glucocorticoid treatment. Glucocorticoid‐induced bone loss is caused primarily by hypofunction and apoptosis of osteoblasts, and secondarily by accelerated bone resorption. To explore the mechanism whereby dexamethasone (Dex) stimulates osteoclastogenesis in the coculture system, we analyzed the effect of Dex on the expression of both mouse osteoprotegerin (OPG) and receptor activator of NF‐κB ligand (RANKL). Dex reduced OPG transcripts and OPG protein secretion by the ST2 osteoblastic cells. Since mainly the c‐Jun homodimer maintains the steady‐state transcription of the OPG gene, we examined the effect of Dex on c‐Jun signaling in ST2 cells. Western blotting disclosed that Dex decreased the amount of phospho‐c‐Jun protein (p‐c‐Jun) and, correspondingly, the amount of the phosphorylated p46 isoform of Jun N‐terminal kinase (JNK). The amount of phospho‐SEK1 also decreased after Dex treatment, while the amounts of phospho‐ERK and p38 remained constant. Among mitogen‐activated protein (MAP) kinase inhibitors, the JNK inhibitor mimicked the inhibitory effect of Dex on OPG promoter activity. On the other hand, Dex treatment per se showed a nominal increase of RANKL gene expression. A part of Dex‐mediated OPG gene suppression was achieved by the suppression of β‐catenin signaling. We speculate therefore that the bone resorptive action of Dex is mediated mainly by the inhibition of OPG by transrepressing the OPG gene through the AP‐1 site, with a reduction (mediated mainly by the decrease in the p46 isoform of JNK) in the proportion of p‐c‐Jun in a JNK‐dependent manner. J. Cell. Biochem. 103: 335–345, 2008. © 2007 Wiley‐Liss, Inc.