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.
Highlights
The trabecular meshwork (TM) is a tissue located in the anterior segment of the eye, which has a major role in regulating intraocular pressure (IOP), by controlling the resistance to aqueous humor (AH) outflow from the eye
Our laboratory previously reported that cathepsin B (CTSB) is constitutively expressed at the cell surface in porcine TM cells and secreted into the culture media in its inactive pro-CTSB
We investigated the presence in the caveolae of components of the proteolytic cascade urokinase plasminogen activator, its receptor, and that of annexin A2 (ANXA2), a proposed binding partner of CTSB and the cell membrane
Summary
The trabecular meshwork (TM) is a tissue located in the anterior segment of the eye, which has a major role in regulating intraocular pressure (IOP), by controlling the resistance to aqueous humor (AH) outflow from the eye. Despite the general belief that matrix metalloproteinases (MMPs) are the only group of enzymes responsible for ECM degradation, emerging evidence in other tissues suggests that other proteases or the coordinated action of several types of proteases, other than just MMPs, participate in bulk matrix degradation and ECM remodeling [11]. In this line, previous studies conducted in our laboratory reported for the first time a role of the lysosomal cysteine protease cathepsin B (CTSB) in intracellular degradation of ECM components in TM cells [12]. We show for the first time that surface CTSB localizes in the caveolae and participates in the pericellular proteolytic cascade in TM cells and TGFβ signaling
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