Proposed Mechanism of Long-Term Intraocular Pressure Lowering With the Bimatoprost Implant.
Stamer W Daniel, Perkumas Kristin M, Kang Min H, Dibas Mohammed, Robinson Michael R, Rhee Douglas J
AI Summary
This study found high-concentration bimatoprost, like that from implants, dramatically upregulates MMPs in outflow tissues, potentially explaining sustained IOP lowering and outflow remodeling, even after drug clearance.
Abstract
Purpose
The purpose of this study was to evaluate the effects of pharmacologically relevant bimatoprost and bimatoprost free acid (BFA) concentrations on matrix metalloproteinase (MMP) gene expression in cells from human aqueous outflow tissues.
Methods
MMP gene expression by human trabecular meshwork (TM), scleral fibroblast (SF), and ciliary muscle (CM) cells exposed to 10 to 1000 µM bimatoprost or 0.1 to 10 µM BFA (intraocular concentrations after intracameral bimatoprost implant and topical bimatoprost dosing, respectively) was measured by polymerase chain reaction array.
Results
Bimatoprost dose-dependently upregulated MMP1 and MMP14 mRNA in all cell types and MMP10 and MMP11 mRNA in TM and CM cells; in TM cells from normal eyes, mean MMP1 mRNA levels were 62.9-fold control levels at 1000 µM bimatoprost. BFA upregulated MMP1 mRNA only in TM and SF cells, to two- to three-fold control levels. The largest changes in extracellular matrix (ECM)-related gene expression by TM cells derived from normal (n = 6) or primary open-angle glaucoma (n = 3) eyes occurred with 1000 µM bimatoprost (statistically significant, ≥50% change for 9-11 of 84 genes on the array, versus 1 gene with 10 µM BFA).
Conclusions
Bimatoprost and BFA had differential effects on MMP/ECM gene expression. Dramatic upregulation in MMP1 and downregulation of fibronectin, which occurred only with bimatoprost at high concentrations observed in bimatoprost implant-treated eyes, may promote sustained outflow tissue remodeling and long-term intraocular pressure reduction beyond the duration of intraocular drug bioavailability. Variability in bimatoprost-stimulated MMP upregulation among cell strains from different donors may help explain differential long-term responses of patients to bimatoprost implant.
MeSH Terms
Shields Classification
Key Concepts6
Bimatoprost dose-dependently upregulated MMP1 and MMP14 mRNA in human trabecular meshwork (TM), scleral fibroblast (SF), and ciliary muscle (CM) cells, and MMP10 and MMP11 mRNA in TM and CM cells.
In human trabecular meshwork (TM) cells from normal eyes, mean MMP1 mRNA levels were 62.9-fold control levels at 1000 µM bimatoprost.
Bimatoprost free acid (BFA) upregulated MMP1 mRNA only in human trabecular meshwork (TM) and scleral fibroblast (SF) cells, to two- to three-fold control levels.
The largest changes in extracellular matrix (ECM)-related gene expression by human trabecular meshwork (TM) cells derived from normal (n = 6) or primary open-angle glaucoma (n = 3) eyes occurred with 1000 µM bimatoprost (statistically significant, ≥50% change for 9-11 of 84 genes on the array), versus 1 gene with 10 µM BFA.
Dramatic upregulation in MMP1 and downregulation of fibronectin, which occurred only with bimatoprost at high concentrations observed in bimatoprost implant-treated eyes, may promote sustained outflow tissue remodeling and long-term intraocular pressure reduction beyond the duration of intraocular drug bioavailability.
Variability in bimatoprost-stimulated MMP upregulation among cell strains from different donors may help explain differential long-term responses of patients to bimatoprost implant.
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