Increased Matrix Metalloproteinases 1, 2, and 3 in the Monkey Uveoscleral Outflow Pathway After Topical Prostaglandin F2α–Isopropyl Ester Treatment

Gaton, Dan D.

doi:10.1001/archopht.119.8.1165

Cited by 132 publications

(88 citation statements)

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“…Their earlier work had shown that following treatment of human ciliary muscle cells in culture with PGF 2α , collagens type I and III were reduced while matrix metalloproteinases 1, 2, 3 and 9 were increased (Lindsey et al, 1996;Lindsey et al, 1997). In vivo, following topical treatment of monkey eyes for 5 days with PGF 2α , collagen types I, III, and IV immunoreactivity in the ciliary muscle and adjacent sclera was reduced (Sagara et al, 1999) while matrix metalloproteinases 1, 2, and 3 were increased (Table 1) (Gaton et al, 2001;Weinreb et al, 2002). Thus the reduction of ciliary muscle extracellular matrix within the interbundle spaces reduces hydraulic resistance to aqueous movement and contributes to the PG-mediated increase of uveoscleral outflow.…”

Section: Prostaglandins and Enhancement Of Uveoscleral Outflowmentioning

confidence: 99%

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Kaufman

2008

Experimental Eye Research

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Several major areas of work by the author and his international collaborators are reviewed. 1) The ciliary muscle in the nonhuman primate eye was disinserted at the scleral spur. Pilocarpine was then ineffective in increasing outflow facility, indicating that ciliary muscle contraction mediated the IOPlowering effect of muscarinic cholinergics. 2) Compounds such as cytochalasins, H-7 and latrunculin A/B, which alter the actin cytoskeleton, cellular contractility and cellular adhesions in cultured trabecular meshwork cells, relaxed trabecular pathway cells and consequently the meshwork itself so as to decrease IOP and enhance trabecular outflow facility in nonhuman primates. Gene transfer approaches utilizing C3 and caldesmon over-expression by viral vectors to target specific steps in the cellular contractility/cytoskeleton/cell adhesion cascades characteristically altered trabecular meshwork cell morphology and increased outflow facility in organ-cultured anterior segments. 3) Prostaglandin F 2α analogues enhanced matrix metalloproteinase production by ciliary muscle cells and scleral fibroblasts, leading to remodeling of the extracellular matrix of the ciliary muscle and sclera and consequently to increased uveoslceral outflow and decreased IOP in primates. 4) The rhesus monkey was an excellent model for human presbyopia, losing the accommodative response to cholinergic stimulation in the same timeframe relative to lifespan. No changes were found in ciliary muscle enzymes involved in acetylcholine biosynthesis or degradation or in muscarinic receptor numbers or affinity. Contractility of isolated ciliary muscle did not diminish with age, but posterior ciliary muscle attachments stiffened, suggesting a possible role in restricting muscle and consequently lens movement during accommodation. A model to reproducibly stimulate accommodation through central stimulation of the Edinger-Westphal nucleus was developed. Goniovideography and ultrasound biomicroscopic techniques allowed real-time recording and analysis of the accommodation-relevant structures. Surgical ablation of the intraocular structures involved in the accommodation response has led to further understanding of their roles and changes with age related to presbyopia. 5) Global collaborations such as those involved in these studies will be essential in the future, as science becomes "bigger".Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The story I will tell is embodied in the title. It is about recognizing questions, asking how and why things happen, recognizing signs along the way, and about focus yet w...

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Section: Prostaglandins and Enhancement Of Uveoscleral Outflowmentioning

confidence: 99%

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Kaufman

2008

Experimental Eye Research

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“…FP-agonists lead to a loss of connective tissue within the ciliary body and increase the expression and/or secretion of MMPs. 8,13,15,33 However, studies have not provided direct evidence that MMPs are involved in the ocular hypotensive response to FP-agonists.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13][14][15] Although studies have shown that MMPs can alter conventional outflow facility in human and animal perfused eyes, 16,17 direct evidence that MMPs participate in the FPagonist-induced modulation of IOP remains to be determined.…”

mentioning

confidence: 99%

Latanoprost-Induced Changes in Rat Intraocular Pressure: Direct or Indirect?

Husain

Yates

Crosson

2008

Journal of Ocular Pharmacology and Therapeutics

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Introduction: The topical application of prostaglandin F 2␣ (FP)-receptor agonists has been shown to significantly lower intraocular pressure (IOP) in humans and is now considered the first-line treatment for ocular hypertension. Despite the prominent role FP-receptor agonists play in the treatment of glaucoma, our understanding of how these agents lower IOP remains incomplete. The present study was designed to evaluate the role of matrix metalloproteinase (MMP) activation and the cytokine, tumor necrosis factor alpha (TNF-␣), in latanoprost-induced changes in IOP. Methods: Changes in IOP following an acute topical administration of latanoprost (60 ng) in normotensive Brown Norway rats were evaluated by means of a commercially available rebound tonometer. To examine the role of MMPs and TNF-␣ in this response, the rats were pretreated with a broad-spectrum MMP inhibitor, GM-6001 (100 g), or the TNF-␣ inhibitor, thalidomide (25 g). Results: The topical administration of latanoprost (60 ng) alone produced a biphasic change in ipsilateral IOP: an initial hypertension (4.21 Ϯ 0.52), followed by a prolonged hypotension (Ϫ4.79 Ϯ 0.65). In rats, pretreatment with GM-6001 blocked the latanoprost-induced reduction in IOP but did not prevent the initial rise in IOP. Pretreatment with thalidomide also blocked the ocular hypotension induced by latanoprost; however, thalidomide pretreatment enhanced the duration of the initial hypertension. Conclusions: These results provide evidence that the secretion and activation of MMPs and the release of TNF-␣ play a central role in the ocular hypotension induced by FP-agonists. The administration of FP-agonists appears to lower IOP directly by inducing the activation of MMPs within the ciliary body, leading to improved uveoscleral outflow and indirectly through the release of TNF-␣ within the ciliary body. Secreted TNF-␣ may then activate TNF-receptors in the uvea and trabecular meshwork, increasing both uveoscleral and conventional outflow.

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“…29,36 Similar anterior segment morphologic changes among the different prostaglandins, 38 suggest similar mechanisms of action on uveoscleral or trabecular outflow. 31 Studies to elucidate cellular mechanisms associated with PG-induced MMP secretion and alterations in calcium signaling pathways in the trabecular meshwork are ongoing.…”

Section: Pharmacodynamic Properties Of Prostaglandin Analogsmentioning

confidence: 96%

“…in human trabecular meshwork cell cultures treated with latanoprost acid for 24 hours, and MMP-1, -2, -3 36 in iris root, ciliary muscle, and adjacent sclera in monkeys may lead to hydrolysis of collagen types I and III (MMP-1), collagen IV and fibronectin (MMP-2), and collagen types III, IV, fibronectin and laminin (MMP-3), resulting in widening of the connective tissue-filled spaces among the ciliary muscle bundles 37 and loss of trabecular meshwork (TM) extracellular matrix, hence increased outflow. 29,36 Similar anterior segment morphologic changes among the different prostaglandins, 38 suggest similar mechanisms of action on uveoscleral or trabecular outflow.…”

Section: Pharmacodynamic Properties Of Prostaglandin Analogsmentioning

confidence: 99%

Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension

Lee

McCluskey

2010

OPTH

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Prostaglandin analogs (PGA) are powerful topical ocular hypotensive agents available for the treatment of elevated intraocular pressure (IOP). Latanoprost 0.005% and travoprost 0.004% are prodrugs and analogs of prostaglandin F2α. Bimatoprost 0.03% is regarded as a prostamide, and debate continues as to whether it is a prodrug. The free acids of all 3 PGAs reduce IOP by enhancing uveoscleral and trabecular outflow via direct effects on ciliary muscle relaxation and remodeling of extracellular matrix. The vast majority of clinical trials demonstrate IOP-lowering superiority of latanoprost, bimatoprost and travoprost compared with timolol 0.5%, brimonidine 0.2%, or dorzolamide 2% monotherapy. Bimatoprost appears to be more efficacious in IOPlowering compared with latanoprost, with weighted mean difference in IOP reduction documented in one meta-analysis of 2.59% to 5.60% from 1-to 6-months study duration. PGAs reduce IOP further when used as adjunctive therapy. Fixed combinations of latanoprost, bimatoprost or travoprost formulated with timolol 0.5% and administered once daily are superior to monotherapy of its constituent parts. PGA have near absence of systemic side effects, although do have other commonly encountered ocular adverse effects. The adverse effects of PGA, and also those found more frequently with bimatoprost use include ocular hyperemia, eyelash growth, and peri-ocular pigmentary changes. Iris pigmentary change is unique to PGA treatment. Once daily administration and near absence of systemic side effects enhances tolerance and compliance. PGAs are often prescribed as first-line treatment for ocular hypertension and open-angle glaucoma.

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Increased Matrix Metalloproteinases 1, 2, and 3 in the Monkey Uveoscleral Outflow Pathway After Topical Prostaglandin F2α–Isopropyl Ester Treatment

Cited by 132 publications

References 20 publications

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

Latanoprost-Induced Changes in Rat Intraocular Pressure: Direct or Indirect?

Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension

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