Matrix Metalloproteinases and Glaucoma Treatment

Robert N. Weinreb, Michael R. Robinson, Mohammed Dibas, W. Daniel Stamer

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.

Original languageEnglish (US)
Pages (from-to)208-228
Number of pages21
JournalJournal of Ocular Pharmacology and Therapeutics
Volume36
Issue number4
DOIs
StatePublished - May 2020
Externally publishedYes

Keywords

  • Bimatoprost
  • Extracellular matrix
  • Glaucoma
  • Intraocular pressure
  • Matrix metalloproteinase
  • Prostaglandin analog

ASJC Scopus subject areas

  • Ophthalmology
  • Pharmacology
  • Pharmacology (medical)

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