Cargando…

Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts

BACKGROUND: Heat shock protein (HSP) 90 functions as a molecular chaperone and is constitutively expressed and induced in response to stress in many cell types. We have previously demonstrated that transforming growth factor-β (TGF-β), the most abundant cytokine in bone cells, induces the expression...

Descripción completa

Detalles Bibliográficos
Autores principales: Kuroyanagi, Gen, Tokuda, Haruhiko, Fujita, Kazuhiko, Kawabata, Tetsu, Sakai, Go, Kim, Woo, Hioki, Tomoyuki, Tachi, Junko, Matsushima-Nishiwaki, Rie, Otsuka, Takanobu, Iida, Hiroki, Kozawa, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134601/
https://www.ncbi.nlm.nih.gov/pubmed/35619094
http://dx.doi.org/10.1186/s12891-022-05419-1
_version_ 1784713798249086976
author Kuroyanagi, Gen
Tokuda, Haruhiko
Fujita, Kazuhiko
Kawabata, Tetsu
Sakai, Go
Kim, Woo
Hioki, Tomoyuki
Tachi, Junko
Matsushima-Nishiwaki, Rie
Otsuka, Takanobu
Iida, Hiroki
Kozawa, Osamu
author_facet Kuroyanagi, Gen
Tokuda, Haruhiko
Fujita, Kazuhiko
Kawabata, Tetsu
Sakai, Go
Kim, Woo
Hioki, Tomoyuki
Tachi, Junko
Matsushima-Nishiwaki, Rie
Otsuka, Takanobu
Iida, Hiroki
Kozawa, Osamu
author_sort Kuroyanagi, Gen
collection PubMed
description BACKGROUND: Heat shock protein (HSP) 90 functions as a molecular chaperone and is constitutively expressed and induced in response to stress in many cell types. We have previously demonstrated that transforming growth factor-β (TGF-β), the most abundant cytokine in bone cells, induces the expression of HSP27 through Smad2, p44/p42 mitogen-activated protein kinase (MAPK), p38 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in mouse osteoblastic MC3T3-E1 cells. This study investigated the effects of HSP90 on the TGF-β-induced HSP27 expression and the underlying mechanism in mouse osteoblastic MC3T3-E1 cells. METHODS: Clonal osteoblastic MC3T3-E1 cells were treated with the HSP90 inhibitors and then stimulated with TGF-β. HSP27 expression and the phosphorylation of Smad2, p44/p42 MAPK, p38 MAPK, and SAPK/JNK were evaluated by western blot analysis. RESULT: HSP90 inhibitors 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib significantly enhanced the TGF-β-induced HSP27 expression. TGF-β inhibitor SB431542 reduced the enhancement by 17-DMAG or onalespib of the TGF-β-induced HSP27 expression levels. HSP90 inhibitors, geldanamycin, onalespib, and 17-DMAG did not affect the TGF-β-stimulated phosphorylation of Smad2. Geldanamycin did not affect the TGF-β-stimulated phosphorylation of p44/p42 MAPK or p38 MAPK but significantly enhanced the TGF-β-stimulated phosphorylation of SAPK/JNK. Onalespib also increased the TGF-β-stimulated phosphorylation of SAPK/JNK. Furthermore, SP600125, a specific inhibitor for SAPK/JNK, significantly suppressed onalespib or geldanamycin’s enhancing effect of the TGF-β-induced HSP27 expression levels. CONCLUSION: Our results strongly suggest that HSP90 inhibitors upregulated the TGF-β-induced HSP27 expression and that these effects of HSP90 inhibitors were mediated through SAPK/JNK pathway in osteoblasts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12891-022-05419-1.
format Online
Article
Text
id pubmed-9134601
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-91346012022-05-27 Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts Kuroyanagi, Gen Tokuda, Haruhiko Fujita, Kazuhiko Kawabata, Tetsu Sakai, Go Kim, Woo Hioki, Tomoyuki Tachi, Junko Matsushima-Nishiwaki, Rie Otsuka, Takanobu Iida, Hiroki Kozawa, Osamu BMC Musculoskelet Disord Research BACKGROUND: Heat shock protein (HSP) 90 functions as a molecular chaperone and is constitutively expressed and induced in response to stress in many cell types. We have previously demonstrated that transforming growth factor-β (TGF-β), the most abundant cytokine in bone cells, induces the expression of HSP27 through Smad2, p44/p42 mitogen-activated protein kinase (MAPK), p38 MAPK, and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in mouse osteoblastic MC3T3-E1 cells. This study investigated the effects of HSP90 on the TGF-β-induced HSP27 expression and the underlying mechanism in mouse osteoblastic MC3T3-E1 cells. METHODS: Clonal osteoblastic MC3T3-E1 cells were treated with the HSP90 inhibitors and then stimulated with TGF-β. HSP27 expression and the phosphorylation of Smad2, p44/p42 MAPK, p38 MAPK, and SAPK/JNK were evaluated by western blot analysis. RESULT: HSP90 inhibitors 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib significantly enhanced the TGF-β-induced HSP27 expression. TGF-β inhibitor SB431542 reduced the enhancement by 17-DMAG or onalespib of the TGF-β-induced HSP27 expression levels. HSP90 inhibitors, geldanamycin, onalespib, and 17-DMAG did not affect the TGF-β-stimulated phosphorylation of Smad2. Geldanamycin did not affect the TGF-β-stimulated phosphorylation of p44/p42 MAPK or p38 MAPK but significantly enhanced the TGF-β-stimulated phosphorylation of SAPK/JNK. Onalespib also increased the TGF-β-stimulated phosphorylation of SAPK/JNK. Furthermore, SP600125, a specific inhibitor for SAPK/JNK, significantly suppressed onalespib or geldanamycin’s enhancing effect of the TGF-β-induced HSP27 expression levels. CONCLUSION: Our results strongly suggest that HSP90 inhibitors upregulated the TGF-β-induced HSP27 expression and that these effects of HSP90 inhibitors were mediated through SAPK/JNK pathway in osteoblasts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12891-022-05419-1. BioMed Central 2022-05-26 /pmc/articles/PMC9134601/ /pubmed/35619094 http://dx.doi.org/10.1186/s12891-022-05419-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kuroyanagi, Gen
Tokuda, Haruhiko
Fujita, Kazuhiko
Kawabata, Tetsu
Sakai, Go
Kim, Woo
Hioki, Tomoyuki
Tachi, Junko
Matsushima-Nishiwaki, Rie
Otsuka, Takanobu
Iida, Hiroki
Kozawa, Osamu
Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title_full Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title_fullStr Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title_full_unstemmed Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title_short Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
title_sort upregulation of tgf-β-induced hsp27 by hsp90 inhibitors in osteoblasts
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134601/
https://www.ncbi.nlm.nih.gov/pubmed/35619094
http://dx.doi.org/10.1186/s12891-022-05419-1
work_keys_str_mv AT kuroyanagigen upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT tokudaharuhiko upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT fujitakazuhiko upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT kawabatatetsu upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT sakaigo upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT kimwoo upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT hiokitomoyuki upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT tachijunko upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT matsushimanishiwakirie upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT otsukatakanobu upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT iidahiroki upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts
AT kozawaosamu upregulationoftgfbinducedhsp27byhsp90inhibitorsinosteoblasts