Open AccessSuppression by HSP90 inhibitors of BMP-4-stimulated osteoprotegerin synthesis in osteoblasts: Attenuation of p70 S6 kinase
Author(s) -
Tetsu Kawabata,
Takanobu Otsuka,
Kazuo Fujita,
Shingo Kainuma,
Naohiro Yamamoto,
Gen Kuroyanagi,
Go Sakai,
Rie MatsushimaNishiwaki,
Osamu Kozawa,
Harukuni Tokuda
Publication year - 2017
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2017.7639
Subject(s) - geldanamycin , osteoprotegerin , hsp90 , bone morphogenetic protein 2 , microbiology and biotechnology , chemistry , osteoblast , kinase , p70 s6 kinase 1 , phosphorylation , heat shock protein , biology , biochemistry , activator (genetics) , protein kinase b , receptor , in vitro , gene
Heat shock protein 90 (HSP90) is an ATP‑dependent ubiquitous molecular chaperon which is important in cell homeostasis. The authors previously demonstrated that bone morphogenetic protein (BMP)‑4 stimulates osteoprotegerin (OPG) production in osteoblast‑like MC3T3‑E1 cells, and that p70 S6 kinase positively regulates the OPG synthesis by BMP‑4. The present study investigated the involvement of HSP90 in the BMP‑4‑stimulated OPG synthesis and the mechanism in MC3T3‑E1 cells. HSP90 inhibitors, 17‑allylamino‑17demethoxy‑geldanamycin (17‑AAG), 17‑dimethylamino‑ethylamino‑17‑demethoxy‑geldanamycin (17‑DMAG) and geldanamycin significantly suppressed the BMP‑4‑stimulated OPG release. Geldanamycin markedly reduced the BMP‑4‑induced mRNA expression of OPG. 17‑AAG and 17‑DMAG significantly attenuated the phosphorylation of p70 S6 kinase induced by BMP‑4 without affecting the BMP‑4‑induced phosphorylation of mothers against decapentaplegic homolog 1/5. The results suggest that HSP90 inhibitors suppress the BMP‑4‑stimulated OPG synthesis in osteoblasts, and that their suppressive effects are exerted through downregulating p70 S6 kinase.