Activation of NF-kappaB by fluid shear stress, but not TNF-alpha, requires focal adhesion kinase in osteoblasts.
Activation of NF-kappaB by fluid shear stress, but not TNF-alpha, requires focal adhesion kinase in osteoblasts.
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DOI：
10.1016/j.bone.2010.03.014
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发表时间：
2010-07
期刊：
影响因子：
4.1
通讯作者：
Pavalko, Fredrick M.
中科院分区：
文献类型：
--
作者：
Young, Suzanne R. L.;Gerard-O'Riley, Rita;Harrington, Maureen;Pavalko, Fredrick M.
当骨受到机械载荷时，由于间质液穿过成骨细胞和骨细胞的膜而产生流体剪切应力（FSS）。这种外部机械负荷刺激细胞质信号分子活性的变化，并改变骨细胞中的基因表达。这一过程被称为机械传导，通过调节骨形成和骨吸收之间的平衡，对维持体内骨健康至关重要。目前的研究重点是粘着斑的作用，整合素介导的细胞附着到细胞外基质的网站，以及它们在骨细胞中作为机械传感器的功能。我们检测了粘着斑和机械传导的关键成分粘着斑激酶（FAK）在成骨细胞中调节FSS和肿瘤坏死因子-α（TNF-α）诱导的核因子-κ B（NF-κB）信号激活中的作用。将永生化的FAK+/+和FAK−/−成骨细胞暴露于振荡流体剪切应力（OFF）周期，并分析NF-κB活化。我们确定FAK是OFF诱导的成骨细胞核转位和NF-κB活化所必需的。此外，我们发现OFF诱导FAK+/+和FAK−/−成骨细胞中IκB激酶（IKKα/β）的磷酸化，但只有FAK+/+成骨细胞表现出NF-κB抑制剂IκBα和IκBβ的降解。OFF不诱导IκBε的降解或FAK+/+和FAK-/-成骨细胞中p105的加工。为了比较FAK在介导OFF诱导的机械转导中的作用与炎症细胞因子对NF-κB的充分表征的激活，我们将FAK+/+和FAK−/−成骨细胞暴露于TNF-α。有趣的是，成骨细胞中TNF-α诱导的NF-κB活化不需要FAK。此外，我们确定TNF-α处理不像OFF那样诱导IκBβ降解。这些数据表明在成骨细胞机械力转导中FAK和NF-κB活化之间存在一种新的关系，并证明了成骨细胞中FSS诱导的NF-κB活化的机制不同于TNF-α诱导的活化。
When bone is mechanically loaded fluid shear stress (FSS) is generated as a result of the movement of interstitial fluid across the membranes of osteoblasts and osteocytes. This external mechanical loading stimulates changes in the activity of cytoplasmic signaling molecules and alters gene expression in bone cells. This process, referred to as mechanotransduction, is vital for maintaining bone health in vivo by regulating the balance between bone formation and bone resorption. This current study focuses on the role of focal adhesions, sites of integrin-mediated cellular attachment to the extracellular matrix, and their proposed function as mechanosensors in bone cells. We examined the role of a key component of focal adhesions and of mechanotransduction, focal adhesion kinase (FAK) in regulation of FSS- and tumor necrosis factor-α (TNF-α)-induced activation of nuclear factor-kappa B (NF-κB) signaling in osteoblasts. Immortalized FAK+/+ and FAK−/− osteoblasts were exposed to periods of oscillatory fluid shear stress (OFF) and NF-κB activation was analyzed. We determined that FAK is required for OFF-induced nuclear translocation and activation of NF-κB in osteoblasts. In addition we found that OFF induced phosphorylation of the IκB kinases (IKKα/β) in both FAK+/+ and FAK−/− osteoblasts, but only FAK+/+ osteoblasts demonstrated the resulting degradation of NF-κB inhibitors IκBα and IκBβ. OFF did not induce the degradation of IκBε or the processing of p105 in either FAK+/+ and FAK−/− osteoblasts. To compare the role of FAK in mediating OFF-induced mechanotransduction to the well characterized activation of NF-κB by inflammatory cytokines, we exposed FAK+/+ and FAK−/− osteoblasts to TNF-α. Interestingly, FAK was not required for TNF-α induced NF-κB activation in osteoblasts. In addition we determined that TNF-α treatment did not induce the degradation of IκBβ as did OFF. These data indicate a novel relationship between FAK and NF-κB activation in osteoblast mechanotransduction and demonstrates that the mechanism of FSS-induced NF-κB activation in osteoblasts differs from the well characterized TNF-α-induced activation.
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影响因子：
15.9
作者：
KHACHIGIAN, LM;RESNICK, N;COLLINS, T
通讯作者：
COLLINS, T
影响因子：
4.8
作者：
Funakoshi-Tago, M;Sonoda, Y;Kasahara, T
通讯作者：
Kasahara, T
DOI：
10.1152/ajpcell.1999.276.5.c1100
发表时间：
1999-05-01
影响因子：
5.5
作者：
Mohan, S;Mohan, N;Sprague, EA
通讯作者：
Sprague, EA
影响因子：
4.1
作者：
Chen, NX;Geist, DJ;Duncan, RL
通讯作者：
Duncan, RL
影响因子：
2.4
作者：
Donahue, TLH;Haut, TR;Jacobs, CR
通讯作者：
Jacobs, CR