Inhibitors of heat shock protein 90 augment endothelin‑1‑induced heat shock protein 27 through the SAPK/JNK signaling pathway in osteoblasts

Fujita,Kazuhiko; Otsuka,Takanobu; Kawabata,Tetsu; Sakai,Go; Matsushima‑Nishiwaki,Rie; Kozawa,Osamu; Tokuda,Haruhiko

doi:10.3892/mmr.2018.8878

Inhibitors of heat shock protein 90 augment endothelin‑1‑induced heat shock protein 27 through the SAPK/JNK signaling pathway in osteoblasts

Authors:
- Kazuhiko Fujita
- Takanobu Otsuka
- Tetsu Kawabata
- Go Sakai
- Rie Matsushima‑Nishiwaki
- Osamu Kozawa
- Haruhiko Tokuda
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Affiliations: Department of Orthopedic Surgery, Nagoya City 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: April 12, 2018 https://doi.org/10.3892/mmr.2018.8878
Pages: 8542-8547

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Abstract

It has been previously reported that endothelin‑1 (ET‑1) stimulates the induction of heat shock protein (HSP) 27 through the activation of p38 mitogen‑activated protein (MAP) kinase and stress‑activated protein kinase/c‑Jun N‑terminal kinase (SAPK/JNK) in osteoblast‑like MC3T3‑E1 cells. The present study investigated whether HSP90, a high‑molecular‑weight HSP, was implicated in the ET‑1‑stimulated HSP27 induction in MC3T3‑E1 cells. The effects of HSP90 inhibitors on the induction of HSP27 were examined. The HSP90 inhibitors geldanamycin and 17‑demethoxygeldanamycin (17‑DMAG) significantly amplified HSP27 induction stimulated by ET‑1 in a dose‑dependent manner. In addition, onalespib (another HSP90 inhibitor) significantly strengthened the ET‑1‑induced HSP27 protein levels. The ET‑1‑stimulated phosphorylation of p38 MAP kinase was minimally affected by geldanamycin, 17‑DMAG or onalespib. Onalespib and 17‑DMAG significantly enhanced the ET‑1‑induced phosphorylation of SAPK/JNK. In addition, SP600125, a SAPK/JNK inhibitor, notably reduced the amplification by onalespib of ET‑1‑induced HSP27. These results suggest that HSP90 limits ET‑1‑stimulated HSP27 induction at a point upstream of SAPK/JNK in osteoblasts. These results suggest that HSP90 may be a novel clinical target for metabolic bone diseases, including osteoporosis.

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