HSP90 inhibitors diminish PDGF-BB-induced migration of osteoblasts via suppression of p44/p42 MAP kinase
HSP90 inhibitors diminish PDGF-BB-induced migration of osteoblasts via suppression of p44/p42 MAP kinase
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DOI：
10.2220/biomedres.40.169
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发表时间：
2019-01-01
影响因子：
1.2
通讯作者：
Kozawa, Osamu
中科院分区：
文献类型：
--
作者：
Kawabata, Tetsu;Tokuda, Haruhiko;Kozawa, Osamu
成骨细胞迁移到破骨细胞吸收的部位是骨重建的重要步骤。然而，成骨细胞迁移的确切机制仍不清楚。我们已经证明，血小板衍生生长因子（PDGF）-BB诱导成骨细胞样MC 3 T3-E1细胞的迁移，通过激活p38丝裂原活化蛋白（MAP）激酶，c-Jun N-末端激酶（JNK）和p44/p42 MAP激酶。热休克蛋白90（HSP 90）是应激条件下蛋白质稳态和细胞生理功能的重要调节因子。本研究采用transwell细胞迁移实验和创伤愈合实验，研究了HSP 90在PDGF-BB刺激的MC 3 T3-E1细胞迁移中的作用，并通过Western blot分析探讨了HSP 90的信号转导机制。Onalb，一种HSP 90抑制剂，显著降低了由两种类型的迁移试验评估的PDGF-BB刺激的迁移。另一种类型的HSP 90抑制剂格尔德霉素也抑制细胞迁移。Onalb显著减弱PDGF-BB诱导的p44/p42 MAP激酶的磷酸化，而不影响p38 MAP激酶或JNK的磷酸化。另外，格尔德霉素可降低PDGF-BB对p44/p42 MAP激酶的磷酸化。综上所述，这些结果强烈表明，HSP 90抑制剂通过减弱p44/p42 MAP激酶活性来抑制PDGF-BB诱导的成骨细胞迁移。
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.