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

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.

Role of MAPK/JNK signaling pathway on the regulation of biological behaviors of MC3T3‑E1 osteoblasts under titanium ion exposure

“…in particular, JnK activity is required for the initiation of early osteogenic differentiation in mesenchymal stem cells (MScs) (31,32). By contrast, attenuation of JnK activity using JnK inhibitors was found to result in increased late stage osteogenic differentiation (33). These findings suggest that the MaPK/JnK signaling pathway serves a vital role throughout different stages of osteogenic differentiation.…”

SIRT3 deficiency increases mitochondrial oxidative stress and promotes migration of retinal pigment epithelial cells

“…7,8,23–25 Additionally, PDGF is a key factor in angiogenesis, which stimulates the migration of various types of cells, including RPE cells. 26–28 PDGF signaling has been reported to be enhanced in diabetes. 29,30 Here we used both high glucose and PDGF to induce RPE cell dysfunction and found that both induced EMT and migration of RPE cells following SIRT3 knockdown.…”