Enhancement by HSP90 inhibitor of PGD2-stimulated HSP27 induction in osteoblasts: Suppression of SAPK/JNK and p38 MAP kinase

Prostaglandins Other Lipid Mediat. 2019 Aug:143:106327. doi: 10.1016/j.prostaglandins.2019.03.002. Epub 2019 Apr 1.

Abstract

Heat shock protein (HSP) 90 that is ubiquitously expressed in various tissues is a major molecular chaperone. We have previously demonstrated that prostaglandin D2 (PGD2), a bone remodeling factor, elicits the expression of HSP27, a small HSP, through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the involvement of HSP90 in the PGD2-stimulated HSP27 induction and the underlying mechanism in MC3T3-E1 cells. Onalespib, an inhibitor of HSP90, significantly enhanced the PGD2-stimulated HSP27 induction. In addition, geldanamycin, another HSP90 inhibitor, potentiated the HSP27 induction. Both onalespib and geldanamycin markedly amplified the PGD2-induced phosphorylation of SAPK/JNK and p38 MAP kinase. SP600125, an inhibitor of SAPK/JNK, and SB203580, an inhibitor of p38 MAP kinase, suppressed the amplification by onalespib of the PGD2-stimulated HSP27 induction. These results strongly suggest that HSP90 plays a negative role in the HSP27 induction stimulated by PGD2 in osteoblasts, and that the inhibitory effect of HSP90 is mediated through the regulation of SAPK/JNK and p38 MAP kinase.

Keywords: HSP27; HSP90; Osteoblast; PGD(2); SAPK/JNK; p38 MAP kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Anthracenes / pharmacology
  • Benzamides / pharmacology
  • Drug Synergism
  • Gene Expression Regulation / drug effects
  • HSP27 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Imidazoles / pharmacology
  • Isoindoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mice
  • Osteoblasts / drug effects*
  • Osteoblasts / metabolism*
  • Phosphorylation / drug effects
  • Prostaglandin D2 / pharmacology*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*

Substances

  • Anthracenes
  • Benzamides
  • HSP27 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Imidazoles
  • Isoindoles
  • Protein Kinase Inhibitors
  • Pyridines
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580
  • (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone
  • Prostaglandin D2