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  • Cathepsin B Localizes in the Caveolae and Participates in the Proteolytic Cascade in Trabecular Meshwork Cells. Potential New Drug Target for the Treatment of Glaucoma.

Cathepsin B Localizes in the Caveolae and Participates in the Proteolytic Cascade in Trabecular Meshwork Cells. Potential New Drug Target for the Treatment of Glaucoma.

Journal of clinical medicine (2021-01-01)
April Nettesheim, Myoung Sup Shim, Angela Dixon, Urmimala Raychaudhuri, Haiyan Gong, Paloma B Liton
ABSTRACT

Extracellular matrix (ECM) deposition in the trabecular meshwork (TM) is one of the hallmarks of glaucoma, a group of human diseases and leading cause of permanent blindness. The molecular mechanisms underlying ECM deposition in the glaucomatous TM are not known, but it is presumed to be a consequence of excessive synthesis of ECM components, decreased proteolytic degradation, or both. Targeting ECM deposition might represent a therapeutic approach to restore outflow facility in glaucoma. Previous work conducted in our laboratory identified the lysosomal enzyme cathepsin B (CTSB) to be expressed on the cellular surface and to be secreted into the culture media in trabecular meshwork (TM) cells. Here, we further investigated the role of CTSB on ECM remodeling and outflow physiology in vitro and in CSTBko mice. Our results indicate that CTSB localizes in the caveolae and participates in the pericellular degradation of ECM in TM cells. We also report here a novel role of CTSB in regulating the expression of PAI-1 and TGFβ/Smad signaling in TM cells vitro and in vivo in CTSBko mice. We propose enhancing CTSB activity as a novel therapeutic target to attenuate fibrosis and ECM deposition in the glaucomatous outflow pathway.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Caveolin-1 antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Monoclonal Anti-Actin, α-Smooth Muscle, clone 1A4, ascites fluid
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Marimastat, ≥98% (HPLC)
Sigma-Aldrich
Anti-Cystatin-C Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
RIPA Buffer
Sigma-Aldrich
E-64d, protease inhibitor
Sigma-Aldrich
Gelatin solution, Type B, 2% in H2O, tissue culture grade, BioReagent, suitable for cell culture