Mechanical loading by fluid shear stress enhances IGF-1 receptor signaling in osteoblasts in a PKCzeta-dependent manner.
Mechanical loading by fluid shear stress enhances IGF-1 receptor signaling in osteoblasts in a PKCzeta-dependent manner.
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DOI：
10.3970/mcb.2007.004.013
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发表时间：
2007-03
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影响因子：
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通讯作者：
Jason W. Triplett;Rita O'Riley;K. Tekulve;S. M. Norvell;F. Pavalko
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文献类型：
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作者：
Jason W. Triplett;Rita O'Riley;K. Tekulve;S. M. Norvell;F. Pavalko
最佳骨生理学的维持需要再吸收旧骨的破骨细胞和存款新骨的成骨细胞的协调活性。骨的机械负荷和骨细胞周围空间内的间质液的运动被认为在维持最佳骨量方面起关键作用。流体运动促进骨形成的一种方式是增强成骨细胞的存活。我们先前已经表明，在体外向成骨细胞施加流体流通过抑制成骨细胞凋亡而赋予保护作用（Pavalko等人，2003年，细胞生理学杂志，194：194-205）。为了研究调节成骨细胞对流体切应力反应的细胞机制，我们研究了MC 3 T3-E1成骨细胞样细胞中流体流动和生长因子之间可能的相互作用。我们发现，胰岛素样生长因子-I（IGF-I）是显着更有效地防止TNF-α诱导的细胞凋亡时，细胞首先受到机械负荷暴露于单向或振荡流体流相比，细胞保持在静态培养。此外，与保持在静态培养中的细胞相比，在经历流体流动的细胞中，响应于IGF-I处理的下游信号传导（包括ERK和Akt活化）增强。此外，我们发现PKC活性对于IGF-IR的流体剪切应力敏化是必不可少的，因为PCKzeta功能的特异性抑制剂阻断了流动增强的IGF-I激活的Akt和ERK磷酸化。总之，我们的研究结果表明，流体剪切应力可能调节IGF-I信号在成骨细胞中的PKC-ζ依赖的方式。
Maintenance of optimal bone physiology requires the coordinated activity of osteoclasts that resorb old bone and osteoblasts that deposit new bone. Mechanical loading of bone and the resulting movement of interstitial fluid within the spaces surrounding bone cells is thought to play a key role is maintaining optimal bone mass. One way in which fluid movement may promote bone formation is by enhancing osteoblast survival. We have shown previously that application of fluid flow to osteoblasts in vitro confers a protective effect by inhibiting osteoblast apoptosis (Pavalko et al., 2003, J. Cell Physiol., 194: 194-205). To investigate the cellular mechanisms that regulate the response of osteoblasts to fluid shear stress, we have examined the possible interaction between fluid flow and growth factors in MC3T3-E1 osteoblast-like cells. We found that insulin-like growth factor-I (IGF-I) was significantly more effective at preventing TNF-alpha-induced apoptosis when cells were first subjected to mechanical loading by exposure to either unidirectional or oscillatory fluid flow compared to cells that were maintained in static culture. Additionally, downstream signaling in response to treatment with IGF-I, including ERK and Akt activation, was enhanced in cells that were subjected to fluid flow, compared to cells maintained in static culture. Furthermore, we found that PKC activity is essential for fluid shear stress sensitization of IGF-IR, since a specific inhibitor of PCKzeta function blocked the flow-enhanced IGF-I-activated Akt and ERK phosphorylation. Together, our results suggest that fluid shear stress may regulate IGF-I signaling in osteoblasts in a PKC-zeta-dependent manner.