HSP90 inhibitors diminish PDGF-BB-induced migration of osteoblasts via suppression of p44/p42 MAP kinase

Tetsu KAWABATA; Haruhiko TOKUDA; Kazuhiko FUJITA; Rie MATSUSHIMA-NISHIWAKI; Go SAKAI; Junko TACHI; Tomoyuki HIOKI; Woo KIM; Hiroki IIDA; Takanobu OTSUKA; Osamu KOZAWA

doi:10.2220/biomedres.40.169

Full Papers

HSP90 inhibitors diminish PDGF-BB-induced migration of osteoblasts via suppression of p44/p42 MAP kinase

Tetsu KAWABATA, Haruhiko TOKUDA, Kazuhiko FUJITA, Rie MATSUSHIMA-NISHIWAKI, Go SAKAI, Junko TACHI, Tomoyuki HIOKI, Woo KIM, Hiroki IIDA, Takanobu OTSUKA, Osamu KOZAWA

Author information

Tetsu KAWABATA
Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences
Department of Pharmacology, Gifu University Graduate School of Medicine
Department of Orthopedic Surgery, Toyokawa City Hospital
Haruhiko TOKUDA
Department of Pharmacology, Gifu University Graduate School of Medicine
Department of Clinical Laboratory/Medical Genome Center Biobank, National Center for Geriatrics and Gerontology
Kazuhiko FUJITA
Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences
Department of Pharmacology, Gifu University Graduate School of Medicine
Rie MATSUSHIMA-NISHIWAKI
Department of Pharmacology, Gifu University Graduate School of Medicine
Go SAKAI
Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences
Department of Pharmacology, Gifu University Graduate School of Medicine
Junko TACHI
Department of Pharmacology, Gifu University Graduate School of Medicine
Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine
Tomoyuki HIOKI
Department of Pharmacology, Gifu University Graduate School of Medicine
Department of Dermatology, Kizawa Memorial Hospital
Woo KIM
Department of Pharmacology, Gifu University Graduate School of Medicine
Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine
Hiroki IIDA
Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine
Takanobu OTSUKA
Department of Orthopedic Surgery, Nagoya City University Graduate School of Medical Sciences
Osamu KOZAWA
Department of Pharmacology, Gifu University Graduate School of Medicine

JOURNAL FREE ACCESS

2019 Volume 40 Issue 4 Pages 169-178

DOI https://doi.org/10.2220/biomedres.40.169

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Abstract

Migration of osteoblasts to the sites resorbed by osteoclasts is an essential step in bone remodeling. However, the exact mechanism of osteoblast migration is still not known. We have shown that platelet-derived growth factor (PDGF)-BB induces the migration of osteoblast-like MC3T3-E1 cells through the activation of p38 mitogen-activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK) and p44/p42 MAP kinase. Evidence is accumulating that heat shock protein 90 (HSP90) acts as a central regulator of proteostasis under stress conditions and physiological cell functions. In the present study, using transwell cell migration assay and wound-healing assay, we investigated the involvement of HSP90 in the PDGF-BB-stimulated migration of MC3T3-E1 cells, and the underlying signaling mechanism estimated by Western blot analyses. Onalespib, an HSP90 inhibitor, significantly reduced the PDGF-BB-stimulated migration evaluated by the two types of migration assays. The cell migration was also suppressed by geldanamycin, another type of HSP90 inhibitor. Onalespib markedly attenuated the PDGF-BB-elicited phosphorylation of p44/p42 MAP kinase without affecting that of p38 MAP kinase or JNK. In addition, the phosphorylation of p44/p42 MAP kinase by PDGF-BB was reduced by geldanamycin. Taken together, these results strongly suggest that HSP90 inhibitors suppress the PDGF-BB-induced osteoblast migration through the attenuation of p44/p42 MAP kinase activity.

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