Connective Tissue Growth Factor Causes Glaucoma by Modifying the Actin Cytoskeleton of the Trabecular Meshwork
Connective Tissue Growth Factor Causes Glaucoma by Modifying the Actin Cytoskeleton of the Trabecular Meshwork
复制标题
DOI：
10.1016/j.ajpath.2012.02.030
复制
发表时间：
2012-06-01
影响因子：
6
通讯作者：
Fuchshofer, Rudolf
中科院分区：
文献类型：
--
作者：
Junglas, Benjamin;Kuespert, Sabrina;Fuchshofer, Rudolf
在原发性开角型青光眼(POAG)病例中，视神经损害的最关键危险因素是小梁网(TM)对房水流出的阻力引起的眼内压(IOP)升高。POAG流出阻力增加的分子机制尚未确定，但可能与转化生长因子转化生长因子-β2有关，后者在POAG患者的房水中含量较高。结缔组织生长因子(CTGF)是一种高结构型TM表达的转化生长因子-β2靶基因。在这项研究中，我们证明了无论是腺病毒介导的还是转基因CTGF在小鼠眼睛中的过表达都会增加RV并导致视神经损伤。CTGF在动物体内诱导TM纤维连接蛋白和α-SMA，而在培养的TM细胞中诱导肌动蛋白应激纤维和收缩。RNA干扰导致CTGF的耗尽导致肌动蛋白细胞骨架的显著衰减。Rho激酶抑制剂使CTGF过度表达的小鼠的眼压可逆地下降到对照仔鼠的水平。总体而言，CTGF对眼压的影响似乎是由TM肌动蛋白细胞骨架的修饰引起的。CTGF过表达的小鼠提供了一种模拟POAG的基本功能和结构方面的模型，并提供了一种分子机制来解释其最关键的危险因素的增加。(Am J Pathol2012,180：2386-2403；http://dx.doi.org/10.1016/j.ajpath.2012.02.030)
The most critical risk factor for optic nerve damage in cases of primary open-angle glaucoma (POAG) is an increased intraocular pressure (IOP) caused by a resistance to aqueous humor outflow in the trabecular meshwork (TM). The molecular pathogenesis of this increase in outflow resistance in POAG has not yet been identified, but it may involve transforming growth factor TGF-beta 2, which is found in higher amounts in the aqueous humor of patients with POAG. Connective tissue growth factor (CTGF) is a TGF-beta 2 target gene with high constitutive TM expression. In this study, we show that either adenoviral-mediated or transgenic CTGF overexpression in the mouse eye increases RV and leads to optic nerve damage. CTGF induces TM fibronectin and alpha-SMA in animals, whereas actin stress fibers and contractility are both induced in cultured TM cells. Depletion of CTGF by RNA interference leads to a marked attenuation of the actin cytoskeleton. Rho kinase inhibitors cause a reversible decline in the IOP of CTGF-overexpressing mice to levels seen in control littermates. Overall, the effects of CTGF on IOP appear to be caused by a modification of the TM actin cytoskeleton. CTGF-overexpressing mice provide a model that mimics the essential functional and structural aspects of POAG and offer a molecular mechanism to explain the increase of its most critical risk factor. (Am J Pathol 2012, 180:2386-2403; http://dx.doi.org/10.1016/j.ajpath.2012.02.030)