Therapeutic Potential of the Molecular Chaperone and Matrix Metalloproteinase Inhibitor Clusterin for Dry Eye.
Therapeutic Potential of the Molecular Chaperone and Matrix Metalloproteinase Inhibitor Clusterin for Dry Eye.
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DOI：
10.3390/ijms22010116
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发表时间：
2020-12-24
影响因子：
5.6
通讯作者：
Wilson MR
中科院分区：
文献类型：
--
作者：
Fini ME;Jeong S;Wilson MR
本文提供的证据支持天然稳态糖蛋白CLU（丛生蛋白）作为治疗干眼的新型治疗剂的潜力。这一想法始于证明基质金属蛋白酶MMP 9是小鼠干眼表损伤所必需的。损伤的特征在于OCLN（occludin）的降解，OCLN是MMP 9的已知底物，也是细胞旁屏障的关键组分。根据这一发现，使用MMP 9作为诱饵进行酵母双杂交筛选，以鉴定涉及的其他蛋白质。CLU是一种强相互作用蛋白，可抑制MMP 9的酶活性。CLU以前被表征为分子伴侣，在液体-组织界面处由上皮细胞显著表达并分泌到体液中，在体液中它保护细胞和组织免受损伤性应激。已经证明，当局部施用CLU以替代从功能障碍的泪液中耗尽的天然蛋白质时，CLU还保护小鼠干眼的眼表面。CLU类似地从人干眼的泪液中耗尽。最新颖和有趣的发现是CLU选择性地与受损的眼表结合。在这个位置，CLU防止上皮细胞死亡和屏障蛋白水解，并抑制自身免疫反应，同时更新顶端上皮细胞层。当以足够高的浓度存在时，CLU还阻断临床上用于诊断干眼症的活体染料的染色。目前的治疗方法都没有这种“保护，密封和愈合”的特性组合。未来的工作将针对人类临床试验，以研究CLU的治疗前景。
Evidence is presented herein supporting the potential of the natural homeostatic glycoprotein CLU (clusterin) as a novel therapeutic for the treatment of dry eye. This idea began with the demonstration that matrix metalloproteinase MMP9 is required for damage to the ocular surface in mouse dry eye. Damage was characterized by degradation of OCLN (occludin), a known substrate of MMP9 and a key component of the paracellular barrier. Following up on this finding, a yeast two-hybrid screen was conducted using MMP9 as the bait to identify other proteins involved. CLU emerged as a strong interacting protein that inhibits the enzymatic activity of MMP9. Previously characterized as a molecular chaperone, CLU is expressed prominently by epithelia at fluid-tissue interfaces and secreted into bodily fluids, where it protects cells and tissues against damaging stress. It was demonstrated that CLU also protects the ocular surface in mouse dry eye when applied topically to replace the natural protein depleted from the dysfunctional tears. CLU is similarly depleted from tears in human dry eye. The most novel and interesting finding was that CLU binds selectively to the damaged ocular surface. In this position, CLU protects against epithelial cell death and barrier proteolysis, and dampens the autoimmune response, while the apical epithelial cell layer is renewed. When present at high enough concentration, CLU also blocks staining by vital dyes used clinically to diagnose dry eye. None of the current therapeutics have this combination of properties to “protect, seal, and heal”. Future work will be directed towards human clinical trials to investigate the therapeutic promise of CLU.
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