CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress.
CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress.
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DOI：
10.1007/s12079-013-0201-y
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发表时间：
2013-08
影响因子：
4.1
通讯作者：
Lyons, Karen M.
中科院分区：
文献类型：
--
作者：
Hall-Glenn, Faith;Aivazi, Armen;Akopyan, Lusi;Ong, Jessica R.;Baxter, Ruth R.;Benya, Paul D.;Goldschmeding, Roel;van Nieuwenhoven, Frans A.;Hunziker, Ernst B.;Lyons, Karen M.
结缔组织生长因子(CTGF/CCN2)是一种利用整合素调节细胞增殖、迁移和存活的基质细胞蛋白。由于严重的软骨发育不良，CCN2的缺失会导致围产儿死亡。在对Ccn2突变小鼠的进一步观察中，我们观察到细胞外基质(ECM)组织的缺陷，并假设CCN2缺失导致的严重软骨发育不良可能与软骨细胞存活缺陷有关。Ccn2突变型生长板软骨细胞内质网增大，提示细胞应激。免疫荧光分析证实了Ccn2突变体的压力增加，而在过度表达Ccn2的转基因小鼠中观察到的压力减少。体外研究表明，Ccn2是软骨细胞中的一个应激反应基因。CCN2−/−软骨细胞中观察到的压力升高是直接的，并部分通过整合素α5介导。在CCN2突变的生长板中，生存标记物NFκB的表达和自噬途径的组成部分减少，提示CCN2可能参与介导软骨细胞的存活。这些数据表明，缺乏基质细胞蛋白会导致细胞压力增加，并突出了CCN2在软骨细胞存活中的新保护作用。CCN2缺失导致的严重软骨发育不良可能是由于软骨细胞应力增加和自噬途径激活缺陷，导致细胞存活率下降。这些作用可能是通过核因子κB(NFκB)作为CCN2/整合素/NFκB信号通路的一部分来介导的。本文的在线版本(doi：10.1007/s120790130201-y)包含补充材料，授权用户可以使用。
CCN2 (connective tissue growth factor (CTGF/CCN2)) is a matricellular protein that utilizes integrins to regulate cell proliferation, migration and survival. The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2−/− chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. These data demonstrate that absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade. The online version of this article (doi:10.1007/s12079-013-0201-y) contains supplementary material, which is available to authorized users.
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