Department of Genetics, UCL Institute of Ophthalmology, London, UK.
Alt-Regen Co., Ltd, Heungdeok IT Valley, Yongin, Republic of Korea.
Prog Retin Eye Res. 2020 Jan;74:100775. doi: 10.1016/j.preteyeres.2019.100775. Epub 2019 Aug 29.
Extracellular matrices (ECMs) are maintained by tightly coupled processes of continuous synthesis and degradation. The degradative arm is mediated by a family of proteolytic enzymes called the matrix metalloproteinases (MMPs). These enzymes are released as latent proteins (pro-MMPs) and on activation are capable of degrading most components of an ECM. Activity of these enzymes is checked by the presence of tissue inhibitors of MMPs (TIMPs) and current opinion holds that the ratio of TIMPs/MMPs determines the relative rate of degradation. Thus, elevated ratios are thought to compromise degradation leading to the accumulation of abnormal ECM material, whilst diminished ratios are thought to lead to excessive ECM degradation (facilitating angiogenesis and the spread of cancer cells). Our recent work has shown this system to be far more complex. MMP species tend to undergo covalent modification leading to homo- and hetero-dimerization and aggregation resulting in the formation of very large macromolecular weight MMP complexes (LMMCs). In addition, the various MMP species also show a bound-free compartmentalisation. The net result of these changes is to reduce the availability of the latent forms of MMPs for the activation process. An assessment of the degradation potential of the MMP system in any tissue must therefore take into account the degree of sequestration of the latent MMP species, a protocol that has not previously been addressed. Taking into consideration the complexities already described, we will present an analysis of the MMP system in two common neurodegenerative disorders, namely age-related macular degeneration (AMD) and Alzheimer's disease (AD).
细胞外基质（ECM）的合成和降解是紧密偶联的过程。降解过程由一系列称为基质金属蛋白酶（MMPs）的蛋白水解酶介导。这些酶以潜伏蛋白（pro-MMPs）的形式释放出来，激活后能够降解 ECM 的大多数成分。这些酶的活性受到组织金属蛋白酶抑制剂（TIMPs）的调节，目前的观点认为 TIMPs/MMPs 的比值决定了降解的相对速度。因此，升高的比值被认为会损害降解，导致异常 ECM 物质的积累，而降低的比值则被认为会导致 ECM 过度降解（促进血管生成和癌细胞的扩散）。我们最近的工作表明，这个系统要复杂得多。MMP 种类往往会发生共价修饰，导致同型和异型二聚体化和聚集，从而形成非常大的高分子量 MMP 复合物（LMMCs）。此外，各种 MMP 种类也表现出结合-游离的区室化。这些变化的净结果是减少了 MMP 潜伏形式用于激活过程的可用性。因此，对任何组织中 MMP 系统的降解潜力进行评估时，必须考虑到潜伏 MMP 种类的隔离程度，这是一个以前尚未解决的问题。考虑到已经描述的复杂性，我们将对两种常见的神经退行性疾病，即年龄相关性黄斑变性（AMD）和阿尔茨海默病（AD）中的 MMP 系统进行分析。
