Chirco Kathleen R, Hazlewood Ralph J, Miller Kathy, Workalemahu Grefachew, Jampol Lee M, Lesser G Robert, Mullins Robert F, Kuehn Markus H, Fingert John H
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA.
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA; Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, IA; Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL.
Mol Vis. 2016 Dec 14;22:1429-1436. eCollection 2016.
The defining feature of glaucoma is excavation of the optic nerve head; however, the mechanism of this loss of tissue is not well understood. We recently discovered a copy number variation upstream of () in a large, autosomal dominant pedigree with a congenital malformation of the optic disc called cavitary optic disc anomaly (CODA). Patients with CODA have abnormal optic discs that exhibit an excavated shape similar to cupping seen in glaucoma. The goal of this study is to characterize the localization of MMP19 within the human optic nerve.
The MMP19 protein in the optic nerve was evaluated with western blot analysis and with immunohistochemistry in sagittal and en face/cross sections of optic nerves obtained from healthy human donor eyes.
The MMP19 protein was detected in the human optic nerve, retina, and RPE/choroid with western blot analysis, with highest expression in the retina and the optic nerve. Using immunohistochemistry, MMP19 was localized within the optic nerve to the extracellular space within the septa that separate bundles of optic nerve axons into fascicles. The presence of MMP19 within the optic nerve septa was further confirmed by the colocalization of MMP19 to this structure with type IV collagen. Strong labeling of MMP19 was also detected in the arachnoid layer of the optic nerve sheath. Finally, immunohistochemistry of the optic nerve cross sections demonstrated that MMP19 shows a peripheral to central gradient, with more abundant labeling along the edges of the optic nerve and in the arachnoid layer than in the center of the nerve.
Abundant MMP19 was detected in the optic nerve head, the primary site of pathology in patients with CODA. The localization of MMP19 to the optic nerve septa is consistent with its predicted secretion and accumulation within the extracellular spaces of this tissue. Moreover, the lateral localization of MMP19 observed in the optic nerve cross sections suggests that it might have a role in regulating adhesion to the optic nerve to the scleral canal and remodeling the extracellular matrix that provides the structural integrity of the optic disc. Dysregulation of MMP19 production might, therefore, undermine the connections between the optic nerve and the scleral canal and cause a collapse of the optic disc and the development of CODA. Similar processes might also be at work in the formation of optic disc cupping in glaucoma.
青光眼的特征性表现是视神经乳头凹陷；然而，这种组织缺失的机制尚不清楚。我们最近在一个患有视神经先天性畸形（称为空洞性视盘异常，CODA）的大型常染色体显性家系中发现了（）上游的拷贝数变异。患有CODA的患者视神经盘异常，呈现出类似于青光眼视盘凹陷的挖掘形状。本研究的目的是确定MMP19在人视神经中的定位。
通过蛋白质免疫印迹分析以及对从健康人类供体眼中获取的视神经矢状面和正面/横断面进行免疫组织化学分析，评估视神经中的MMP19蛋白。
通过蛋白质免疫印迹分析在人视神经、视网膜和视网膜色素上皮/脉络膜中检测到MMP19蛋白，在视网膜和视神经中表达最高。使用免疫组织化学方法，MMP19在视神经中定位于将视神经轴突束分隔成小束的间隔内的细胞外空间。MMP19与IV型胶原在该结构中的共定位进一步证实了其在视神经间隔中的存在。在视神经鞘的蛛网膜层中也检测到MMP19的强标记。最后，对视神经横断面的免疫组织化学分析表明，MMP19呈现从周边到中央的梯度，沿视神经边缘和蛛网膜层的标记比神经中心更丰富。
在CODA患者的主要病理部位视神经乳头中检测到大量MMP19。MMP19定位于视神经间隔与其在该组织细胞外空间中的预测分泌和积累一致。此外，在视神经横断面中观察到的MMP19的外侧定位表明，它可能在调节视神经与巩膜管的粘附以及重塑提供视盘结构完整性的细胞外基质中发挥作用。因此，MMP19产生的失调可能会破坏视神经与巩膜管之间的连接，并导致视盘塌陷和CODA的发展。类似的过程也可能在青光眼视盘凹陷的形成中起作用。
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