Matrix metalloproteinases in neuroinflammation
Matrix metalloproteinases in neuroinflammation
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DOI：
10.1002/glia.10108
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发表时间：
2002-09-01
期刊：
影响因子：
6.2
通讯作者：
Rosenberg, GA
中科院分区：
文献类型：
--
作者：
Rosenberg, GA
基质金属蛋白酶（MMP）是中性蛋白酶的基因家族，其在正常发育、伤口愈合和多种病理过程（包括转移性癌细胞的扩散、关节炎性关节破坏、动脉粥样硬化和神经炎症）中是重要的。在中枢神经系统（CNS）中，MMPs已被证明降解基底膜的组分，导致血脑屏障（BBB）的破坏，并在许多神经系统疾病中促成神经炎症反应。脑细胞表达组成型和诱导型MMPs以响应细胞应激。MMPs受到严格调控，以避免不必要的蛋白水解。作为非活性酶分泌，MMPs需要被其他蛋白酶和自由基激活。MMPs是更大类的金属蛋白酶（MP）的一部分，其包括最近发现的亚当斯（去整合素和金属蛋白酶结构域）和ADAMTS（去整合素和金属蛋白酶血小板反应蛋白）家族。MP在细胞表面和细胞外基质内具有复杂的作用。在细胞表面，它们作为脱落酶，释放生长因子，死亡受体和死亡诱导配体，使它们在细胞存活和死亡中发挥重要作用。金属蛋白酶组织抑制剂（TIMPs）是调节MMPs活性的内源性抑制剂。合成抑制剂已被开发用于治疗关节炎和癌症。这些基于羟基酸盐的化合物已显示出减少实验性过敏性脑脊髓炎（EAE）、实验性过敏性神经炎（EAN）、脑缺血、脑内出血以及病毒和细菌感染中的损伤。MP具有有益和有害的作用;了解它们在各种CNS损伤中的表达将允许在神经系统疾病的治疗中使用MMP抑制剂。
Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMS (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders.