de Iongh R U, Wederell E, Lovicu F J, McAvoy J W
Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Australia.
Cells Tissues Organs. 2005;179(1-2):43-55. doi: 10.1159/000084508.
The vertebrate lens has a distinct polarity and structure that are regulated by growth factors resident in the ocular media. Fibroblast growth factors, in concert with other growth factors, are key regulators of lens fiber cell differentiation. While members of the transforming growth factor (TGFbeta) superfamily have also been implicated to play a role in lens fiber differentiation, inappropriate TGFbeta signaling in the anterior lens epithelial cells results in an epithelial-mesenchymal transition (EMT) that bears morphological and molecular resemblance to forms of human cataract, including anterior subcapsular (ASC) and posterior capsule opacification (PCO; also known as secondary cataract or after-cataract), which occurs after cataract surgery. Numerous in vitro and in vivo studies indicate that this TGFbeta-induced EMT is part of a wound healing response in lens epithelial cells and is characterized by induced expression of numerous extracellular matrix proteins (laminin, collagens I, III, tenascin, fibronectin, proteoglycans), intermediate filaments (desmin, alpha-smooth muscle actin) and various integrins (alpha2, alpha5, alpha7B), as well as the loss of epithelial genes [Pax6, Cx43, CP49, alpha-crystallin, E-cadherin, zonula occludens-1 protein (ZO-1)]. The signaling pathways involved in initiating the EMT seem to primarily involve the Smad-dependent pathway, whereby TGFbeta binding to specific high affinity cell surface receptors activates the receptor-Smad/Smad4 complex. Recent studies implicate other factors [such as fibroblast growth factor (FGFs), hepatocyte growth factor, integrins], present in the lens and ocular environment, in the pathogenesis of ASC and PCO. For example, FGF signaling can augment many of the effects of TGFbeta, and integrin signaling, possibly via ILK, appears to mediate some of the morphological features of EMT initiated by TGFbeta. Increasing attention is now being directed at the network of signaling pathways that effect the EMT in lens epithelial cells, with the aim of identifying potential therapeutic targets to inhibit cataract, particularly PCO, which remains a significant clinical problem in ophthalmology.
脊椎动物晶状体具有独特的极性和结构，这些特性受眼内介质中存在的生长因子调控。成纤维细胞生长因子与其他生长因子协同作用，是晶状体纤维细胞分化的关键调节因子。虽然转化生长因子（TGFβ）超家族成员也被认为在晶状体纤维分化中发挥作用，但晶状体前上皮细胞中不适当的TGFβ信号传导会导致上皮-间充质转化（EMT），其在形态和分子水平上与人白内障的某些形式相似，包括前囊下白内障（ASC）和后囊膜混浊（PCO；也称为继发性白内障或后发性白内障），后者发生在白内障手术后。大量的体外和体内研究表明，这种由TGFβ诱导的EMT是晶状体上皮细胞伤口愈合反应的一部分，其特征是诱导表达多种细胞外基质蛋白（层粘连蛋白、I型、III型胶原蛋白、腱生蛋白、纤连蛋白、蛋白聚糖）、中间丝（结蛋白、α-平滑肌肌动蛋白）和各种整合素（α2、α5、α7B），同时上皮基因（Pax6、Cx43、CP49、α-晶体蛋白、E-钙黏蛋白、紧密连接蛋白-1（ZO-1））表达缺失。启动EMT的信号通路似乎主要涉及Smad依赖途径，即TGFβ与特定的高亲和力细胞表面受体结合会激活受体-Smad/Smad4复合物。最近的研究表明，晶状体和眼内环境中存在的其他因子[如成纤维细胞生长因子（FGFs）、肝细胞生长因子、整合素]与ASC和PCO的发病机制有关。例如，FGF信号传导可增强TGFβ的许多作用，整合素信号传导可能通过整合素连接激酶（ILK）介导TGFβ引发的EMT的一些形态学特征。目前，越来越多的注意力集中在影响晶状体上皮细胞EMT的信号通路网络上，目的是确定潜在的治疗靶点以抑制白内障，尤其是PCO，这在眼科领域仍然是一个重大的临床问题。
