Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor alpha-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to Ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of beta-catenin signaling.
Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor alpha-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to Ambient IGF, leading to phosphatidylinositol 3-kinase/AKT-dependent Wnt/LRP5 receptor-independent activation of beta-catenin signaling.
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DOI：
10.1074/jbc.m109.027086
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发表时间：
2010-03-19
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影响因子：
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通讯作者：
Price JS
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作者：
Sunters A;Armstrong VJ;Zaman G;Kypta RM;Kawano Y;Lanyon LE;Price JS
骨骼调整其质量和结构以承受日常活动负荷的能力来自于它们的常驻细胞对产生的压力做出适当反应的能力。为了阐明骨细胞应变响应的机制，我们在体外研究了原代小鼠成骨细胞和UMR-106成骨样细胞对单个动态应变的反应。这刺激了一系列的事件，包括激活胰岛素样生长因子I受体，磷脂酰肌醇3-激酶介导的AKT的磷酸化，抑制GSK-3β，增加β-连环蛋白的激活，以及相关的淋巴增强因子/T细胞因子介导的转录。这一途径的启动不涉及Wnt/LRP5/FrizzledR，也不会导致IGF转录增加。菌株对IGF-IR的影响被外源DES-(1-3)IGF-I模拟，并被IGF-IR抑制剂H1356阻断。抑制与菌株相关的前列腺素和一氧化氮的产生会抑制与菌株相关的(和基础的)AKT活性，但它们单独的异位给药不能模仿它。胰岛素样生长因子-IR的激活需要雌激素受体α(ER-α)，与胰岛素样生长因子-1R有物理联系。ER阻滞剂ICI 182,780增加了激活这一级联反应所需的DES-(1-3)IGF-I的浓度，而雌激素既抑制基础AKT活性，也抑制DES-(1-3)IGF-I激活AKT。这些数据表明，在成骨细胞中，应变相关的事件最初级联，其中应变激活胰岛素样生长因子-IR，与ERα相关，从而启动依赖于磷脂酰肌醇3-激酶/Akt的β-连环蛋白的激活，并改变淋巴增强因子/T细胞因子的转录。这一级联反应需要前列腺素/一氧化氮的产生，并且不依赖于Wnt/LRP5。
The capacity of bones to adjust their mass and architecture to withstand the loads of everyday activity derives from the ability of their resident cells to respond appropriately to the strains engendered. To elucidate the mechanisms of strain responsiveness in bone cells, we investigated in vitro the responses of primary mouse osteoblasts and UMR-106 osteoblast-like cells to a single period of dynamic strain. This stimulates a cascade of events, including activation of insulin-like growth factor I receptor (IGF-IR), phosphatidylinositol 3-kinase-mediated phosphorylation of AKT, inhibition of GSK-3β, increased activation of β-catenin, and associated lymphoid-enhancing factor/T cell factor-mediated transcription. Initiation of this pathway does not involve the Wnt/LRP5/Frizzled receptor and does not culminate in increased IGF transcription. The effect of strain on IGF-IR is mimicked by exogenous des-(1–3)IGF-I and is blocked by the IGF-IR inhibitor H1356. Inhibition of strain-related prostanoid and nitric oxide production inhibits strain-related (and basal) AKT activity, but their separate ectopic administration does not mimic it. Strain-related IGF-IR activation of AKT requires estrogen receptor α (ERα) with which IGF-1R physically associates. The ER blocker ICI 182,780 increases the concentration of des-(1–3)IGF-I necessary to activate this cascade, whereas estrogen inhibits both basal AKT activity and its activation by des-(1–3)IGF-I. These data suggest an initial cascade of strain-related events in osteoblasts in which strain activates IGF-IR, in association with ERα, so initiating phosphatidylinositol 3-kinase/AKT-dependent activation of β-catenin and altered lymphoid-enhancing factor/T cell factor transcription. This cascade requires prostanoid/nitric oxide production and is independent of Wnt/LRP5.