Influence of Actin Cytoskeletal Integrity on Matrix Metalloproteinase-2 Activation in Cultured Human Trabecular Meshwork Cells

Sanka, Krishna; Maddala, Rupalatha; Epstein, David L.; Rao, Ponugoti Vasantha

doi:10.1167/iovs.06-1089

Cited by 51 publications

(51 citation statements)

References 54 publications

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“…(Santas et al 2003) A recent study showing effects of cytoskeletal modifying agents on matrix metalloproteinases (MMPs) further adds to the complexity of assigning direct roles for the cells or ECM. (Sanka et al 2007) The various GAG-modifying studies mentioned above suggest a direct ECM contribution to the outflow resistance. The initiation of ECM turnover in the TM, mediated by members of the MMP family, also increases outflow facility.…”

Section: Segmental Flowmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

417

443

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The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

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Section: Segmental Flowmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

417

443

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“…[33][34][35] In addition, a direct cellular contribution, possibly beyond the ECM turnover involvement, appears to affect the outflow resistance in some manner that is currently only partially understood. 10,[36][37][38][39][40][41][42] A large number of cellular cytoskeletal tension/relaxation studies showing acute and more sustained effects on outflow facility have been reported. Numerous studies where cell-related properties, for example, nitric oxide and eNOS, RhoA GTPase, are associated with direct or indirect cellular effects on outflow, suggest additional complexity.…”

Section: How Could the Iop Homeostatic Process Work?mentioning

confidence: 99%

“…Many cytoskeletal manipulations have dramatic effects on both outflow facility and TM cell behavior. 36,37,39,44 Although most of the cytoskeletal research has not been directly applicable to the IOP homeostatic pressure responses, several studies have shown clear effects that may relate to the IOP homeostatic mechanism. 40,[44][45][46][47] Focal ECM Turnover Initially, it was not fully appreciated that the IOP homeostatic ECM turnover events needed to be highly constrained and very focal.…”

Section: Signal Transduction and Cellular Responses To Stretching/prementioning

confidence: 99%

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Acott

Kelley

Keller

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

147

150

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Although glaucoma is a relatively common blinding disease, most people do not develop glaucoma. A robust intraocular pressure (IOP) homeostatic mechanism keeps ocular pressures within relatively narrow acceptable bounds throughout most peoples' lives. The trabecular meshwork and/or Schlemm's canal inner wall cells respond to sustained IOP elevation and adjust the aqueous humor outflow resistance to restore IOP to acceptable levels. It appears that the cells sense IOP elevations as mechanical stretch or distortion of the actual outflow resistance and respond by initiating a complex extracellular matrix (ECM) turnover process that takes several days to complete. Although considerable information pertinent to this process is available, many aspects of the IOP homeostatic process remain to be elucidated. Components and mechanisms beyond ECM turnover could also be relevant to IOP homeostasis, but will not be addressed in detail here. Known aspects of the IOP homeostasis process as well as possible ways that it might function and impact glaucoma are discussed. Glaucoma Glaucoma is an optic neuropathy characterized by a distinctive pattern of permanent visual field loss. 1,2Optic disk cupping is also a diagnostic parameter. Elevated intraocular pressure (IOP) is the primary risk factor for glaucomatous optic nerve damage and reducing pressure remains the only treatable component of disease progression.2,3 Although glaucoma is a relatively common blinding disease affecting over 67 million persons worldwide, [3][4][5] it is noteworthy that only 2%-8% of people actually develop this disease within their lifetime and most only at advanced ages. The implication of this observation is that some very efficacious mechanism exists to maintain IOP within acceptable ranges throughout the life of most people. 6Intraocular Pressure IOP is maintained primarily by changes in the aqueous humor outflow resistance, which is thought to reside predominantly within the cribriform or juxtacanalicular ( JCT) region of the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC).6-10 Aqueous humor inflow rates are relatively stable and are not pressure dependent, until very high pressures are achieved. 11,12 Although outflow through the alternative or uveoscleral pathway is clearly important, most of the outflow in humans is through the conventional TM/SC route. 2,7,8,12,13 IOP HomeostasisFor our purposes, in this study, we will define IOP homeostasis as corrective adjustments of the aqueous humor outflow resistance, which occur in direct response to sustained pressure changes and which maintain IOP within acceptable physiological ranges.We hypothesize that the flow resistance within the conventional outflow pathway is continually being adjusted with time frames measured in many hours and that sustained pressure changes serve as a guide for the direction and extent of homeostatic resistance modifications. Since the outflow resistance is thought to be comprised primarily of extracellular matrix (ECM) 6,7,9,10,14,15 and sinc...

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“…Alternatively, endocannabinoids and lysophospholipids impact cell contractility, while lysophospholipids also impact cell-cell junction assembly. To complicate these relationships, it appears that manipulations that impact cellular components that mediate contractility influence MMP activation in different cell types, including TM cells [133]. Unknown to a large extent, however, is the relative role of receptor subtypes and their location in the conventional tract, the degree of cross-talk between mediators and the relative contribution of each potential mechanism to total outflow resistance.…”

Section: Five-year Viewmentioning

confidence: 99%

Endogenous bioactive lipids and the regulation of conventional outflow facility

Wan

Woodward

Stamer

2008

Expert Review of Ophthalmology

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SummaryPerturbation of paracrine signaling within the human conventional outflow pathway influences tissue homeostasis and outflow function. For example, exogenous introduction of the bioactive lipids, sphingosine-1-phosphate, anandamide or prostaglandin F 2α , to conventional outflow tissues alters the rate of drainage of aqueous humor through the trabecular meshwork, and into Schlemm's canal. This review summarizes recent data that characterizes endogenous bioactive lipids, their receptors and associated signaling partners in the conventional outflow tract. We also discuss the potential of targeting such signaling pathways as a strategy for the development of therapeutics to treat ocular hypertension and glaucoma.

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Influence of Actin Cytoskeletal Integrity on Matrix Metalloproteinase-2 Activation in Cultured Human Trabecular Meshwork Cells

Cited by 51 publications

References 54 publications

Extracellular matrix in the trabecular meshwork

Extracellular matrix in the trabecular meshwork

Intraocular Pressure Homeostasis: Maintaining Balance in a High-Pressure Environment

Endogenous bioactive lipids and the regulation of conventional outflow facility

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