Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway.
Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway.
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DOI：
10.3390/cells10112864
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发表时间：
2021-10-24
期刊：
影响因子：
6
通讯作者：
Pattabiraman PP
中科院分区：
文献类型：
--
作者：
Soundararajan A;Ghag SA;Vuda SS;Wang T;Pattabiraman PP
细胞外基质（ECM）和肌动蛋白在小梁网（TM）流出通路中的动态平衡在眼内压（IOP）调节中起着关键作用。我们研究了组织蛋白酶K（CTSK），一种溶酶体半胱氨酸蛋白酶和一种有效的胶原酶，在TM流出通路和IOP调节中对ECM调节和肌动蛋白细胞骨架重排的作用。最初，我们发现CTSK是负性调节的病理应激已知升高IOP。此外，使用balicatib（CTSK的药理学细胞渗透性抑制剂）灭活CTSK，由于TM流出通路中ECM样胶原-1A水平升高和过度沉积导致IOP升高。CTSK活性的丧失导致肌动蛋白通过肌成束蛋白和黏着斑蛋白重组以及通过磷酸-cofilin抑制肌动蛋白解聚而成束。CTSK的组成性表达通过减少磷酸化cofilin减少ECM并增加肌动蛋白解聚，负性调节活性TGFβ2的可用性，并降低α-平滑肌肌动蛋白（αSMA）的水平，表明CTSK的抗纤维化作用。总之，这些观察结果，第一次，证明了CTSK在IOP调节的意义，通过维持ECM稳态和肌动蛋白细胞因子介导的收缩特性的TM流出途径。
The homeostasis of extracellular matrix (ECM) and actin dynamics in the trabecular meshwork (TM) outflow pathway plays a critical role in intraocular pressure (IOP) regulation. We studied the role of cathepsin K (CTSK), a lysosomal cysteine protease and a potent collagenase, on ECM modulation and actin cytoskeleton rearrangements in the TM outflow pathway and the regulation of IOP. Initially, we found that CTSK was negatively regulated by pathological stressors known to elevate IOP. Further, inactivating CTSK using balicatib, a pharmacological cell-permeable inhibitor of CTSK, resulted in IOP elevation due to increased levels and excessive deposition of ECM-like collagen-1A in the TM outflow pathway. The loss of CTSK activity resulted in actin-bundling via fascin and vinculin reorganization and by inhibiting actin depolymerization via phospho-cofilin. Contrarily, constitutive expression of CTSK decreased ECM and increased actin depolymerization by decreasing phospho-cofilin, negatively regulated the availability of active TGFβ2, and reduced the levels of alpha-smooth muscle actin (αSMA), indicating an antifibrotic action of CTSK. In conclusion, these observations, for the first time, demonstrate the significance of CTSK in IOP regulation by maintaining the ECM homeostasis and actin cytoskeleton-mediated contractile properties of the TM outflow pathway.
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影响因子：
1.8
作者：
Christensen J;Shastri VP
通讯作者：
Shastri VP
DOI：
10.1073/pnas.1414126111
发表时间：
2014-12-09
影响因子：
11.1
作者：
Aguda, Adeleke H.;Panwar, Preety;Broemme, Dieter
通讯作者：
Broemme, Dieter
DOI：
10.1007/s004170000241
发表时间：
2001-02-01
影响因子：
2.7
作者：
Inatani, M;Tanihara, H;Honda, Y
通讯作者：
Honda, Y
影响因子：
4.4
作者：
Choritz, Lars;Machert, Maren;Thieme, Hagen
通讯作者：
Thieme, Hagen
影响因子：
6.1
作者：
Brömme D;Lecaille F
通讯作者：
Lecaille F