Agapova Olga A, Kaufman Paul L, Lucarelli Mark J, Gabelt B'Ann T, Hernandez M R
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8096, St. Louis, MO 63110, USA.
Brain Res. 2003 Mar 28;967(1-2):132-43. doi: 10.1016/s0006-8993(02)04234-8.
Extracellular matrix (ECM) remodeling after neuronal injury and reactive gliosis is carried out by activation of matrix metalloproteinases (MMPs) regulated by their tissue inhibitors (TIMPs). In glaucoma, there is a loss of retinal ganglion cells and extensive ECM remodeling (cupping) at the level of the optic nerve head, frequently associated with elevated intraocular pressure. To determine whether ECM remodeling in the glaucomatous optic nerve head occurs in response to loss of axons or to elevated intraocular pressure we compared the patterns of MMP and TIMP expression in the eyes of monkeys with laser-induced glaucoma or with optic nerve transection. MT1-MMP and MMP1 expression was markedly increased in reactive astrocytes in optic nerve heads with experimental glaucoma but not in the optic nerve head of transected eyes. In normal control eyes retinal ganglion cells expressed MMP2, TIMP1 and TIMP2 constitutively, and the proteins were detected in their axons. At the site of transection, MT1-MMP, MMP1, MMP2, TIMP1 and TIMP2 were expressed by reactive astrocytes. Inflammatory cells, fibroblasts and reactive astrocytes at the transected site expressed MMP3 and MMP9, which were undetectable in the retina and optic nerve head in any condition. Constitutive expression of MMP2, TIMP1 and TIMP2 in retinal ganglion cells suggests a role in maintenance of synaptic integrity and plasticity and maintenance of the periaxonal space. Increased MMP1 and MT1-MMP1 expression in the glaucomatous optic nerve head is specific to tissue remodeling due to elevated intraocular pressure and not secondary to loss of axons.
神经元损伤和反应性胶质增生后的细胞外基质（ECM）重塑是通过基质金属蛋白酶（MMPs）的激活来实现的，而MMPs受其组织抑制剂（TIMPs）的调节。在青光眼中，视网膜神经节细胞会丢失，并且在视神经乳头水平会发生广泛的ECM重塑（杯状凹陷），这通常与眼内压升高有关。为了确定青光眼视神经乳头中的ECM重塑是对轴突丧失还是眼内压升高的反应，我们比较了激光诱导性青光眼或视神经横断的猴子眼中MMP和TIMP的表达模式。在实验性青光眼的视神经乳头中的反应性星形胶质细胞中，MT1-MMP和MMP1的表达明显增加，但在横断眼的视神经乳头中则没有增加。在正常对照眼中，视网膜神经节细胞组成性表达MMP2、TIMP1和TIMP2，并且在它们的轴突中检测到这些蛋白。在横断部位，反应性星形胶质细胞表达MT1-MMP、MMP1、MMP2、TIMP1和TIMP2。横断部位的炎性细胞、成纤维细胞和反应性星形胶质细胞表达MMP3和MMP9，在任何情况下视网膜和视神经乳头中均未检测到这两种蛋白。视网膜神经节细胞中MMP2、TIMP1和TIMP2的组成性表达表明它们在维持突触完整性和可塑性以及轴突周围间隙的维持中发挥作用。青光眼视神经乳头中MMP1和MT1-MMP1表达的增加是眼内压升高导致组织重塑的特异性表现，而非轴突丧失的继发结果。
