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Abstract
Heat shock protein 70 (HSP70) is a ubiquitously expressed molecular chaperone in a variety of cells including osteoblasts. We previously showed that insulin-like growth factor-I (IGF-I) elicits migration of osteoblast-like MC3T3-E1 cells through the activation of phosphatidylinositol 3-kinase/Akt and p44/p42 mitogen-activated protein (MAP) kinase. In the present study, we investigated the effects of HSP70 inhibitors on the IGF-I-elicited migration of these cells and the mechanism involved. The IGF-I-stimulated osteoblast migration evaluated by a wound-healing assay and by a transwell cell migration was significantly reduced by VER-155008 and YM-08, which are both HSP70 inhibitors. VER-155008 markedly suppressed the IGF-I-induced phosphorylation of p44/p42 MAP kinase without affecting that of Akt. In conclusion, our results strongly suggest that the HSP70 inhibitor reduces the IGF-I-elicited migration of osteoblasts via the p44/p42 MAP kinase.
Highlights
It is firmly established that bone metabolism is regulated cooperatively by bone-forming osteoblasts and bone-resorbing osteoclasts and that bone tissue is consistently regenerated through bone remodeling [1,2]
We investigated the effects of Heat shock protein 70 (HSP70) inhibitors on the insulin-like growth factor-I (IGF-I)-elicited migration of osteoblast-like MC3T3-E1 cells and the underlying mechanism
We examined the effect of YM-08, which is another inhibitor of HSP70 [23], on the IGF-Istimulated migration of MC3T3-E1 cells by a wound-healing assay
Summary
It is firmly established that bone metabolism is regulated cooperatively by bone-forming osteoblasts and bone-resorbing osteoclasts and that bone tissue is consistently regenerated through bone remodeling [1,2]. Insulin-like growth factor-I (IGF-I), which is embedded abundantly in the bone matrix, plays a crucial role in the regulation of bone metabolism [6,7]. As for the effect of IGF-I on osteoblast migration, IGF-I activates Akt and stimulates migration of osteoblast-like MC3T3-E1 cells as a chemotactic factor [10]. In our study [11], we have demonstrated that p44/p42 MAP kinase and phosphatidylinositol 3-kinase/Akt act as positive regulators in the IGF-I-induced migration of osteoblast-like MC3T3-E1 cells. We investigated the effects of HSP70 inhibitors on the IGF-I-elicited migration of osteoblast-like MC3T3-E1 cells and the underlying mechanism. We show that the HSP70 inhibitor suppresses the IGF-I-elicited migration of osteoblasts through attenuation of the p44/p42 MAP kinase pathway
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