Tissue Transglutaminase Expression and Activity in Normal and Glaucomatous Human Trabecular Meshwork Cells and Tissues

Tovar-Vidales, Tara; Roque, Rouel S.; Clark, Abbot F.; Wordinger, Robert J.

doi:10.1167/iovs.07-0835

Cited by 91 publications

(90 citation statements)

References 45 publications

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“…87,88 This stiffness could also modulate TM cell sensing, responsiveness, or direct behavior. [89][90][91][92][93][94][95] An array of other related ECM effects are also likely involved, but IOP homeostatic relationships are not well defined for any of these. 15,67,68,96,97 …”

Section: Iop Homeostasis and Glaucomamentioning

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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Section: Iop Homeostasis and Glaucomamentioning

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

View full text Add to dashboard Cite

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“…[48][49][50][51] Transglutaminase-2 (TGM2), also regulated by YAP, is also important to ECM deposition and turnover and has been reported to be significantly upregulated in glaucoma or with glucocorticoid treatment of HTM cells. 52 YAP/TAZ are localized to the nucleus when cells are cultured on stiffer substrates. 35 The nuclear localization of YAP/TAZ and subsequent transcriptional activity on such genes as CTGF, TGF-b, and TGM2 can thus be hypothesized to play a significant role in the initiation and progression of glaucoma.…”

mentioning

confidence: 99%

Role of Substratum Stiffness in Modulating Genes Associated with Extracellular Matrix and Mechanotransducers YAP and TAZ

Raghunathan

Morgan

Dreier

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Primary open-angle glaucoma is characterized by increased resistance to aqueous humor outflow and a stiffer human trabecular meshwork (HTM). Two Yorkie homologues, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif, encoded by WWTR1 (TAZ), are mechanotransducers of the extracellular-microenvironment and coactivators of transcription. Here, we explore how substratum stiffness modulates the YAP/TAZ pathway and extracellular matrix genes in HTM cells and how this may be play a role in the onset and progression of glaucoma.METHODS. HTM cells from normal donors were cultured on hydrogels mimicking the stiffness of normal (5 kPa) and glaucomatous (75 kPa) HTM. Changes in expression of YAP/ TAZ related genes and steroid responsiveness were determined. Additionally, transglutaminase-2 expression was determined after YAP silencing.RESULTS. YAP and TAZ are both expressed in human trabecular meshwork cells. In vitro, YAP and TAZ were inversely regulated by substratum stiffness. YAP and 14-3-3r were downregulated to different extents on stiffer substrates; TAZ, tissue transglutaminase (TGM2), and soluble frizzled-related protein-1 (sFRP-1) were significantly upregulated. CTGF expression appeared to be altered differentially by both YAP and TAZ. Myocilin and angiopoietin-like 7 expression in response to dexamethasone was more pronounced on stiffer substrates. We demonstrated a direct effect by YAP on TGM2 when YAP was silenced by small interfering RNA.CONCLUSIONS. The expression of YAP/TAZ and ECM-relatedgenes is impacted on physiologically relevant substrates. YAP was upregulated in cells on softer substrates. Stiffer substrates resulted in upregulation of canonical Wnt modulators, TAZ and sFRP-1, and thus may influence the progression of glaucoma. These results demonstrate the importance of YAP/TAZ in the HTM and suggest their role in glaucoma. (Invest Ophthalmol Vis Sci.

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“…In addition, tissue transglutaminase 2 (TGM2) catalyzes the post-translational modification of ECM molecules including fibronectin. The levels and activity of TGM2 were increased in glaucoma TM cells [45]. Both of these studies suggest that increased cross-linking may impact the mechanical properties of glaucomatous TM tissue.…”

Section: Alterations In the Jct With Aging And Glaucomamentioning

confidence: 79%

“…Therefore, there appears to be a reciprocal relationship between outflow resistance and HA: as HA concentration is reduced, outflow resistance increases [44]. This points to HA as a critical The role of ECM cross-linking molecules in normal and POAG TM has also been studied [45,46]. A certain degree of cross-linking is beneficial to the tissue since cross-linking confers greater resistance of the ECM to physical degradation and protease digestion, which results in increased mechanical strength of the tissue.…”

Section: Alterations In the Jct With Aging And Glaucomamentioning

confidence: 99%

“…The role of ECM cross-linking molecules in normal and POAG TM has also been studied [45,46]. A certain degree of cross-linking is beneficial to the tissue since cross-linking confers greater resistance of the ECM to physical degradation and protease digestion, which results in increased mechanical strength of the tissue.…”

Section: Alterations In the Jct With Aging And Glaucomamentioning

confidence: 99%

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The Juxtacanalicular Region of Ocular Trabecular Meshwork: A Tissue with a Unique Extracellular Matrix and Specialized Function

2013

J Ocul Biol

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The trabecular meshwork (TM) is a filter-like tissue located in the anterior segment of the eye. It is composed of a series of fenestrated beams through which aqueous humor flows to exit the anterior chamber via Schlemm's canal. The primary function of the TM is to regulate the flow of aqueous humor in order to establish intraocular pressure (IOP). Dysregulated aqueous humor outflow causes elevated IOP, which is a primary risk factor for glaucoma. The region of the TM implicated in establishing IOP lies adjacent to Schlemm's canal and is called the juxtacanalicular tissue (JCT) or cribriform region. Recent advanced light microscopy studies suggest that the JCT can be subdivided into inner and outer zones based on the localization of certain extracellular matrix (ECM) molecules. By comparing the ECM of the JCT to other connectives tissues and disease processes, this review outlines the evidence for two new concepts in TM biology: (1) continuous maintenance ECM remodeling, which may be critical in order to preserve open aqueous humor flow channels by releasing trapped debris and associated ECM fragments from the outflow pathways; (2) the JCT ECM as a barrier to functionally isolate the aqueous outflow channels. The ECM surrounding the outflow channels in the JCT may function to sequester small active regulatory molecules and prevent them from aberrantly modulating outflow resistance. These adaptations point to a distinctive tissue that has evolved transient ECM remodeling processes in order to regulate aqueous humor outflow and maintain rigorous control of IOP. KeywordsExtracellular matrix; Trabecular meshwork; Glaucoma; Outflow resistance; Intraocular pressure The Juxtacanalicular Trabecular MeshworkThe TM is a triangular-shaped tissue that is located in the scleral sulcus of the anterior chamber of the eye. The TM can be divided into separate regions based on anatomical location, which differ in both structure and function: the uveal and corneoscleral meshworks, the insert region, and the juxtacanalicular region (JCT) (Figure 1). The corneoscleral and uveal meshworks are comprised of fenestrated beams of lamellae, with large intertrabecular spaces between adjacent sheets [1]. These intertrabecular spaces decrease in size and the lamellae become slightly flatter as the corneoscleral meshwork transitions into the JCT region. The JCT is the deepest area of the tissue that lies adjacent to the inner wall (IW) endothelium of Schlemm's canal [2]. This area of tissue is approximately 2-20 μm thick. Unlike the uveal and corneoscleral meshworks, the JCT is not arranged into lamellae structures, but rather it is composed of a loosely arranged extracellular matrix (ECM) in which a sparse number of JCT cells are embedded [2]. These cells are separated from the IW endothelium, although they can extend processes that communicate with both IW cells and TM cells resident in the corneoscleral meshwork [3,4]. The ECM is highly hydrated and provides a conduit for aqueous humor to traverse the JCT and exit the anterior cham...

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Tissue Transglutaminase Expression and Activity in Normal and Glaucomatous Human Trabecular Meshwork Cells and Tissues

Cited by 91 publications

References 45 publications

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

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

Role of Substratum Stiffness in Modulating Genes Associated with Extracellular Matrix and Mechanotransducers YAP and TAZ

The Juxtacanalicular Region of Ocular Trabecular Meshwork: A Tissue with a Unique Extracellular Matrix and Specialized Function

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