Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

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 ac...

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Autores principales:	Avinash Soundararajan, Sachin Anil Ghag, Sai Supriya Vuda, Ting Wang, Padmanabhan Paranji Pattabiraman
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cathepsin K trabecular meshwork intraocular pressure extracellular matrix actin cytoskeleton Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b8ad48cc340c46349b3583c1244398dd
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spelling	oai:doaj.org-article:b8ad48cc340c46349b3583c1244398dd2021-11-25T17:08:13ZCathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway10.3390/cells101128642073-4409https://doaj.org/article/b8ad48cc340c46349b3583c1244398dd2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2864https://doaj.org/toc/2073-4409The 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.Avinash SoundararajanSachin Anil GhagSai Supriya VudaTing WangPadmanabhan Paranji PattabiramanMDPI AGarticlecathepsin Ktrabecular meshworkintraocular pressureextracellular matrixactin cytoskeletonBiology (General)QH301-705.5ENCells, Vol 10, Iss 2864, p 2864 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cathepsin K trabecular meshwork intraocular pressure extracellular matrix actin cytoskeleton Biology (General) QH301-705.5
spellingShingle	cathepsin K trabecular meshwork intraocular pressure extracellular matrix actin cytoskeleton Biology (General) QH301-705.5 Avinash Soundararajan Sachin Anil Ghag Sai Supriya Vuda Ting Wang Padmanabhan Paranji Pattabiraman Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
description	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.
format	article
author	Avinash Soundararajan Sachin Anil Ghag Sai Supriya Vuda Ting Wang Padmanabhan Paranji Pattabiraman
author_facet	Avinash Soundararajan Sachin Anil Ghag Sai Supriya Vuda Ting Wang Padmanabhan Paranji Pattabiraman
author_sort	Avinash Soundararajan
title	Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
title_short	Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
title_full	Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
title_fullStr	Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
title_full_unstemmed	Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway
title_sort	cathepsin k regulates intraocular pressure by modulating extracellular matrix remodeling and actin-bundling in the trabecular meshwork outflow pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b8ad48cc340c46349b3583c1244398dd
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Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow Pathway

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