Ultrasound induces cyclooxygenase-2 expression through integrin, integrin-linked kinase, Akt, NF-κB and p300 pathway in human chondrocytes
Ultrasound induces cyclooxygenase-2 expression through integrin, integrin-linked kinase, Akt, NF-κB and p300 pathway in human chondrocytes
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DOI：
10.1016/j.cellsig.2007.07.006
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发表时间：
2007-11-01
影响因子：
4.8
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
--
作者：
Hsu, Horng-Chaung;Fong, Yi-Chin;Tang, Chih-Hsin
在动物模型和临床研究中已经表明，超声（US）刺激加速骨折愈合。然而，超声在软骨细胞中产生的精确分子事件还没有很好地阐明。我们发现，如流式细胞术分析所示，超声刺激瞬时增加了人软骨细胞中α 2、α 5、β 1或β 3整合素的表面表达，但不增加α 3或α 4整合素的表面表达。超声刺激增加前列腺素E-2的形成以及环氧合酶-2（考克斯-2）的蛋白和mRNA水平。在机制水平上，抗整合素β 1和β 3抗体或β 1和β 3整合素小干扰RNA减弱了US诱导的考克斯-2表达。整合素连接激酶（ILK）抑制剂（KP-392）、Akt抑制剂、NF-κ B抑制剂（PDTC）或I κ B蛋白酶抑制剂（TPCK）也可抑制US的增强作用。US刺激促进ILK的激酶活性，Akt的磷酸化。此外，US刺激还诱导IKK α/β磷酸化、276 I κ B α磷酸化、IKB α降解、p65在Ser（276）处的磷酸化、p65和p50从胞质溶胶易位至细胞核以及κ B-荧光素酶活性。超声可增强p65与NF-κ B元件的结合，以及p300的募集和考克斯-2启动子上p50乙酰化的增强。综上所述，我们的结果提供了证据表明，超声刺激通过整合素/ILK/Akt/NF-κ B和p300信号通路增加软骨细胞中考克斯-2的表达。(C)2007爱思唯尔公司All rights reserved.
It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and in clinical studies. However, the precise molecular events generated by US in chondrocytes have not been clarified well. Here we found that US stimulation transiently increased the surface expression of alpha 2, alpha 5, beta 1 or beta 3 but not alpha 3 or alpha 4 integrins in human chondrocytes, as shown by flow cytometric analysis. US stimulation increased prostaglandin E-2 formation as well as the protein and mRNA levels of cyclooxygenase-2 (COX-2). At the mechanistic level, anti-integrin beta 1 and beta 3 antibodies or beta 1 and beta 3 integrin small interference RNA attenuated the US-induced COX-2 expression. Integrin-linked kinase (ILK) inhibitor (KP-392), Akt inhibitor, NF-kappa B inhibitor (PDTC) or I kappa B protease inhibitor (TPCK) also inhibited the potentiating action of US. US stimulation promotes kinase activity of ILK, phosphorylation of Akt. In addition, US stimulation also induces IKK alpha/beta phosphorylation, 276 I kappa B alpha phosphorylation, IKB alpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus, and kappa B-luciferase activity. The binding of p65 to the NF-kappa B element, as well as the recruitment of p300 and the enhancement of p50 acetylation on the COX-2 promoter was enhanced by US. Taken together, our results provide evidence that US stimulation increases COX-2 expression in chondrocytes via the integrin/ILK/Akt/NF-kappa B and p300 signaling pathway. (C) 2007 Elsevier Inc. All rights reserved.