Tensile strain increases expression of CCN2 and COL2A1 by activating TGF-β-Smad2/3 pathway in chondrocytic cells
Tensile strain increases expression of CCN2 and COL2A1 by activating TGF-β-Smad2/3 pathway in chondrocytic cells
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DOI：
10.1016/j.jbiomech.2013.03.028
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发表时间：
2013-05-31
影响因子：
2.4
通讯作者：
Ozaki, Toshifumi
中科院分区：
文献类型：
--
作者：
Furumatsu, Takayuki;Matsumoto, Emi;Ozaki, Toshifumi
生理性机械应力刺激软骨形成基因的表达，例如多功能生长因子CYR 61/CTGF/NOV（CCN）2和α 1（II）胶原（COL 2A 1），并维持软骨稳态。在我们以前的研究中，周期性拉伸应变（CTS）诱导转化生长因子（TGF）-β受体调节Smad 2/3和主软骨形成转录因子Srytype HMG盒（SOX）9的核转位。然而，在CCN 2和COL 2A 1的转录调控中，拉伸介导的Smad激活的确切机制仍不清楚。在这里，我们假设，CTS可能会诱导TGF-β 1的释放和刺激Smad依赖的软骨形成基因在人软骨细胞SW 1353细胞的表达。单轴CTS（0.5 Hz，5%应变）刺激SW 1353细胞中CCN 2和COL 2A 1的基因表达，并诱导TGF-β 1分泌。CTS刺激CCN 2合成和Smad 2/3和SOX 9的核转位。此外，CTS增加了磷酸化Smad 2/3和SOX 9之间的复合物形成。在荧光素酶报告基因检测中，CIS和Smad 3协同增强CCN 2启动子活性。染色质免疫沉淀显示，CTS增加Smad 2/3与CCN 2启动子和COL 2A 1增强子的相互作用。我们的研究结果表明，CTS通过与Smad 2/3激活相关的TGF-β 1释放表观遗传刺激CCN 2转录，并通过SOX 9和Smad 2/3之间的复合物形成增强COL 2A 1表达。(C)2013爱思唯尔有限公司保留所有权利。
Physiologic mechanical stress stimulates expression of chondrogenic genes, such as multifunctional growth factor CYR61/CTGF/NOV (CCN) 2 and alpha 1(II) collagen (COL2A1), and maintains cartilage home-ostasis. In our previous studies, cyclic tensile strain (CTS) induces nuclear translocation of transforming growth factor (TGF)-beta receptor-regulated Smad2/3 and the master chondrogenic transcription factor Srytype HMG box (SOX) 9. However, the precise mechanism of stretch-mediated Smad activation remains unclear in transcriptional regulation of CCN2 and COL2A1. Here we hypothesized that CTS may induce TGF-beta 1 release and stimulate Smad-dependent chondrogenic gene expression in human chondrocytic SW1353 cells. Uni-axial CTS (0.5 Hz, 5% strain) stimulated gene expression of CCN2 and COL2A1 in SW1353 cells, and induced TGF-beta 1 secretion. CCN2 synthesis and nuclear translocalization of Smad2/3 and SOX9 were stimulated by CTS. In addition, CTS increased the complex formation between phosphorylated Smad2/3 and SOX9. The CCN2 promoter activity was cooperatively enhanced by CIS and Smad3 in luciferase reporter assay. Chromatin immunoprecipitation revealed that CTS increased Smad2/3 interaction with the CCN2 promoter and the COL2A1 enhancer. Our results suggest that CTS epigenetically stimulates CCN2 transcription via TGF-beta 1 release associated with Smad2/3 activation and enhances COL2A1 expression through the complex formation between SOX9 and Smad2/3. (C) 2013 Elsevier Ltd. All rights reserved.