Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9.
Selective Expression of Osteopontin in ALS-resistant Motor Neurons is a Critical Determinant of Late Phase Neurodegeneration Mediated by Matrix Metalloproteinase-9.
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DOI：
10.1038/srep27354
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发表时间：
2016-06-06
影响因子：
4.6
通讯作者：
Misawa H
中科院分区：
文献类型：
--
作者：
Morisaki Y;Niikura M;Watanabe M;Onishi K;Tanabe S;Moriwaki Y;Okuda T;Ohara S;Murayama S;Takao M;Uchida S;Yamanaka K;Misawa H
运动神经元（MN）亚型之间的差异易损性是肌萎缩侧索硬化（ALS）的基本特征：快疲劳（FF）MN比快抗疲劳（FR）或慢（S）MN更易损。这种选择性的脆弱性的原因仍然是个谜。我们在这里报告，细胞外基质（ECM）蛋白骨桥蛋白（OPN）选择性表达的FR和S MN和ALS耐药的运动池，而基质金属蛋白酶-9（MMP-9）选择性表达的FF MN。在三个ALS小鼠模型和一个人ALS患者中，OPN作为ECM中的细胞外颗粒分泌和积累。在SOD 1G 93 A小鼠中，OPN/MMP-9双阳性标记重构的FR和S MN，其注定在最终死亡之前补偿丢失的FF MN。SOD 1G 93 A小鼠中OPN的基因消融延迟了疾病发作，但随后加速了疾病进展。在表达ChAT的Neuro 2a细胞中，OPN通过αvβ3整合素诱导MMP-9上调，并以非细胞自主的方式诱导CD 44介导的星形胶质细胞迁移和小胶质细胞吞噬。我们的研究结果表明，在ALS小鼠模型中，FR/S MNs表达的OPN通过αvβ3整合素上调MMP-9参与第二波神经退行性变。MN亚群中OPN/MMP-9表达谱的差异部分解释了ALS中选择性MN脆弱性。
Differential vulnerability among motor neuron (MN) subtypes is a fundamental feature of amyotrophic lateral sclerosis (ALS): fast-fatigable (FF) MNs are more vulnerable than fast fatigue-resistant (FR) or slow (S) MNs. The reason for this selective vulnerability remains enigmatic. We report here that the extracellular matrix (ECM) protein osteopontin (OPN) is selectively expressed by FR and S MNs and ALS-resistant motor pools, whereas matrix metalloproteinase-9 (MMP-9) is selectively expressed by FF MNs. OPN is secreted and accumulated as extracellular granules in ECM in three ALS mouse models and a human ALS patient. In SOD1G93A mice, OPN/MMP-9 double positivity marks remodeled FR and S MNs destined to compensate for lost FF MNs before ultimately dying. Genetic ablation of OPN in SOD1G93A mice delayed disease onset but then accelerated disease progression. OPN induced MMP-9 up-regulation via αvβ3 integrin in ChAT-expressing Neuro2a cells, and also induced CD44-mediated astrocyte migration and microglial phagocytosis in a non-cell-autonomous manner. Our results demonstrate that OPN expressed by FR/S MNs is involved in the second-wave neurodegeneration by up-regulating MMP-9 through αvβ3 integrin in the mouse model of ALS. The differences in OPN/MMP-9 expression profiles in MN subsets partially explain the selective MN vulnerability in ALS.