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.

中文翻译：

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HSP90抑制剂通过抑制p44 / p42 MAP激酶减少了PDGF-BB诱导的成骨细胞迁移。

成骨细胞向破骨细胞吸收的部位的迁移是骨重塑的重要步骤。然而，成骨细胞迁移的确切机制仍然未知。我们已经表明，血小板源性生长因子（PDGF）-BB通过激活p38丝裂原激活蛋白（MAP）激酶，c-Jun N端激酶（JNK）和P38诱导成骨细胞样MC3T3-E1细胞的迁移。 p44 / p42 MAP激酶。越来越多的证据表明，在压力条件和生理细胞功能下，热激蛋白90（HSP90）可以作为蛋白稳态的中央调节剂。在本研究中，我们使用跨孔细胞迁移测定和伤口愈合测定，调查了HSP90在PDGF-BB刺激的MC3T3-E1细胞迁移中的参与，以及通过Western blot分析估计的潜在信号传导机制。奥纳斯匹布 HSP90抑制剂可显着降低PDGF-BB刺激的通过两种类型的迁移分析评估的迁移。格尔德霉素（另一种HSP90抑制剂）也抑制了细胞迁移。Onalespib显着减弱了PDGF-BB引起的p44 / p42 MAP激酶的磷酸化，而没有影响p38 MAP激酶或JNK的磷酸化。另外，格尔德霉素减少了PDGF-BB对p44 / p42 MAP激酶的磷酸化作用。综上所述，这些结果强烈表明，HSP90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。Onalespib显着减弱了PDGF-BB引起的p44 / p42 MAP激酶的磷酸化，而没有影响p38 MAP激酶或JNK的磷酸化。另外，格尔德霉素减少了PDGF-BB对p44 / p42 MAP激酶的磷酸化作用。综上所述，这些结果强烈表明，HSP90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。Onalespib显着减弱了PDGF-BB引起的p44 / p42 MAP激酶的磷酸化，而没有影响p38 MAP激酶或JNK的磷酸化。另外，格尔德霉素减少了PDGF-BB对p44 / p42 MAP激酶的磷酸化作用。综上所述，这些结果强烈表明，HSP90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。