Suppression by HSP90 inhibitors of BMP‑4‑stimulated osteoprotegerin synthesis in osteoblasts: Attenuation of p70 S6 kinase

Kawabata,Tetsu; Otsuka,Takanobu; Fujita,Kazuhiko; Kainuma,Shingo; Yamamoto,Naohiro; Kuroyanagi,Gen; Sakai,Go; Matsushima‑Nishiwaki,Rie; Kozawa,Osamu; Tokuda,Haruhiko

doi:10.3892/mmr.2017.7639

Suppression by HSP90 inhibitors of BMP‑4‑stimulated osteoprotegerin synthesis in osteoblasts: Attenuation of p70 S6 kinase

Authors:
- Tetsu Kawabata
- Takanobu Otsuka
- Kazuhiko Fujita
- Shingo Kainuma
- Naohiro Yamamoto
- Gen Kuroyanagi
- Go Sakai
- Rie Matsushima‑Nishiwaki
- Osamu Kozawa
- Haruhiko Tokuda
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Affiliations: Department of Orthopedic Surgery, Nagoya University Graduate School of Medical Sciences, Nagoya 467‑8601, Japan, Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan
Published online on: September 27, 2017 https://doi.org/10.3892/mmr.2017.7639
Pages: 8507-8512

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Abstract

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.

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