Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts
Abstract 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 ex...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | BMC Musculoskeletal Disorders |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12891-022-05419-1 |
| _version_ | 1811258880324272128 |
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| author | Gen Kuroyanagi Haruhiko Tokuda Kazuhiko Fujita Tetsu Kawabata Go Sakai Woo Kim Tomoyuki Hioki Junko Tachi Rie Matsushima-Nishiwaki Takanobu Otsuka Hiroki Iida Osamu Kozawa |
| author_facet | Gen Kuroyanagi Haruhiko Tokuda Kazuhiko Fujita Tetsu Kawabata Go Sakai Woo Kim Tomoyuki Hioki Junko Tachi Rie Matsushima-Nishiwaki Takanobu Otsuka Hiroki Iida Osamu Kozawa |
| author_sort | Gen Kuroyanagi |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T18:21:06Z |
| format | Article |
| id | doaj.art-d7dab7483c244fb296d6568b40a34bef |
| institution | Directory Open Access Journal |
| issn | 1471-2474 |
| language | English |
| last_indexed | 2024-04-12T18:21:06Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Musculoskeletal Disorders |
| spelling | doaj.art-d7dab7483c244fb296d6568b40a34bef2022-12-22T03:21:26ZengBMCBMC Musculoskeletal Disorders1471-24742022-05-0123111110.1186/s12891-022-05419-1Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblastsGen Kuroyanagi0Haruhiko Tokuda1Kazuhiko Fujita2Tetsu Kawabata3Go Sakai4Woo Kim5Tomoyuki Hioki6Junko Tachi7Rie Matsushima-Nishiwaki8Takanobu Otsuka9Hiroki Iida10Osamu Kozawa11Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical SciencesDepartment of Pharmacology, Gifu University Graduate School of MedicineDepartment of Orthopedic Surgery, Nagoya City University Graduate School of Medical SciencesDepartment of Orthopedic Surgery, Nagoya City University Graduate School of Medical SciencesDepartment of Orthopedic Surgery, Nagoya City University Graduate School of Medical SciencesDepartment of Pharmacology, Gifu University Graduate School of MedicineDepartment of Pharmacology, Gifu University Graduate School of MedicineDepartment of Pharmacology, Gifu University Graduate School of MedicineDepartment of Pharmacology, Gifu University Graduate School of MedicineDepartment of Orthopedic Surgery, Nagoya City University Graduate School of Medical SciencesDepartment of Anesthesiology and Pain Medicine, Gifu University Graduate School of MedicineDepartment of Pharmacology, Gifu University Graduate School of MedicineAbstract 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.https://doi.org/10.1186/s12891-022-05419-1Heat shock proteinHSP90HSP90 inhibitorHSP27TGF-βSAPK/JNK |
| spellingShingle | Gen Kuroyanagi Haruhiko Tokuda Kazuhiko Fujita Tetsu Kawabata Go Sakai Woo Kim Tomoyuki Hioki Junko Tachi Rie Matsushima-Nishiwaki Takanobu Otsuka Hiroki Iida Osamu Kozawa Upregulation of TGF-β-induced HSP27 by HSP90 inhibitors in osteoblasts BMC Musculoskeletal Disorders Heat shock protein HSP90 HSP90 inhibitor HSP27 TGF-β SAPK/JNK |
| 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 | Heat shock protein HSP90 HSP90 inhibitor HSP27 TGF-β SAPK/JNK |
| url | https://doi.org/10.1186/s12891-022-05419-1 |
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