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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MDPI AG
2021-10-01
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:37:40Z |
| format | Article |
| id | doaj.art-b8ad48cc340c46349b3583c1244398dd |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T05:37:40Z |
| publishDate | 2021-10-01 |
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| spelling | doaj.art-b8ad48cc340c46349b3583c1244398dd2023-11-22T22:47:52ZengMDPI AGCells2073-44092021-10-011011286410.3390/cells10112864Cathepsin K Regulates Intraocular Pressure by Modulating Extracellular Matrix Remodeling and Actin-Bundling in the Trabecular Meshwork Outflow PathwayAvinash Soundararajan0Sachin Anil Ghag1Sai Supriya Vuda2Ting Wang3Padmanabhan Paranji Pattabiraman4Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1160 West Michigan Street, Indianapolis, IN 46202-5209, USAGlick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1160 West Michigan Street, Indianapolis, IN 46202-5209, USAGlick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1160 West Michigan Street, Indianapolis, IN 46202-5209, USAGlick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1160 West Michigan Street, Indianapolis, IN 46202-5209, USAGlick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1160 West Michigan Street, Indianapolis, IN 46202-5209, USAThe 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.https://www.mdpi.com/2073-4409/10/11/2864cathepsin Ktrabecular meshworkintraocular pressureextracellular matrixactin cytoskeleton |
| spellingShingle | 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 Cells cathepsin K trabecular meshwork intraocular pressure extracellular matrix actin cytoskeleton |
| title | 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_short | 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 |
| topic | cathepsin K trabecular meshwork intraocular pressure extracellular matrix actin cytoskeleton |
| url | https://www.mdpi.com/2073-4409/10/11/2864 |
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