Matrix metalloproteinasen in glaucoom: doelwitten voor nieuwe therapieën?

Matrix metalloproteinases (MMPs), a family of Zn2+-dependent proteases, were originally named after their ability to cleave and remodel the extracellular matrix (ECM), however, their substrate repertoire has proven to be much broader, comprising other proteinases, growth factors, signaling molecules, cell surface receptors, and even intracellular targets. By proteolytic cleavage, MMPs modify the structure and activity of these substrates, and add a complex extra dimension of biological control. As a result, MMPs are important regulatory nodes in the protease web, a complex network of interactions that regulates protease activities and determines the functional state of the proteome and cell activity. Deregulated MMP activity is a common characteristic of many diseases, including neurodegenerative disorders such as glaucoma, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, etc. Nevertheless, despite their detrimental impact during central nervous system (CNS) pathology, there is ample evidence corroborating MMPs as fine regulators of CNS physiology, and well-balanced MMP activity is instrumental to CNS development, plasticity and repair. Multiple studies in glaucoma patients and in animal models of spontaneous and experimentally induced glaucoma, reported changes in the expression and activity of several MMPs in the retina, optic nerve, aqueous humor and trabecular meshwork. These data have led to the hypothesis that MMPs might be involved in glaucoma onset and/or disease progression. However, reports are conflicting and research aiming at providing a clear definition of their causative role is lacking. With this work, we intend to contribute to a better understanding of the role of MMPs during glaucoma pathogenesis and to the development of much-needed novel therapeutic approaches to treat this optic neuropathy. Indeed, with more than 65 million patients worldwide, and still on the increase, glaucoma is and will be a major concern for ophthalmologists today and in the future. Current baroprotective therapies allow to reduce intraocular pressure in the majority of glaucoma patients and to halt -yet not reverse- disease progression. Nevertheless, a sizeable percentage of patients do not benefit from this therapeutic approach, and, as no alternatives are available, experience progressive vision loss. Four MMPs, namely MMP-2, MMP-3, MMP-9 and MT1-MMP, are the subject of different experimental approaches, aiming to answer the central question: “Can we identify MMPs as novel targets for the development of baroprotective, neuroprotective and/or regenerative therapeutic strategies for the treatment of glaucoma?”status: publishe