Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-β1 and dexamethasone in vitro

Flügel-Koch, Cassandra; Ohlmann, Andreas; Fuchshofer, Rudolf; Welge–Lüßen, Ulrich; Tamm, Ernst R.

doi:10.1016/j.exer.2004.07.005

Cited by 114 publications

(90 citation statements)

References 60 publications

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“…14 TSP1 has been implicated in the pathogenesis of glaucoma because its expression is increased in one third of patients with primary open-angle glaucoma (POAG). 16 Consistent with this correlation are the findings that TSP1 expression is increased in situations of fibrosis, wound healing, and other circumstances in which there is significant matrix production. 14,17,18 The creation of mice deficient in various matricellular proteins has also helped investigate their potential role in IOP regulation.…”

supporting

confidence: 75%

Thrombospondin-1 (TSP1)–Null and TSP2-Null Mice Exhibit Lower Intraocular Pressures

Haddadin

Kang

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP).METHODS. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM).RESULTS. Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs.CONCLUSIONS. TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding. (Invest Ophthalmol Vis Sci. 2012;53:6708-6717)

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supporting

confidence: 75%

Thrombospondin-1 (TSP1)–Null and TSP2-Null Mice Exhibit Lower Intraocular Pressures

Haddadin

Kang

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…(Tripathi, RC et al 1994;Welge-Lussen et al 1999;Li et al 2000;Welge-Lussen et al 2000;Lutjen-Drecoll and Rohen 2001;Gottanka et al 2004) Immunostaining for thrombospondin 1 is observed throughout the TM, with the greatest density in the JCT region. (Flugel-Koch et al 2004) Tenascin C or hexabrachion is another matricellular protein expressed in the TM. (Chen et al 2005;Vittal et al 2005;Keller et al 2007b) Tenascin C is composed of numerous repeat binding domains and forms a hexamer by disulfide bonding of the N-terminal tenascin assembly domain using heptad repeats (Fig.…”

Section: Matricellular Proteinsmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

415

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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“…121,150,151 TSP-1 and TSP-2 are both expressed in human TM, 75,121 but TSP-1 localizes to the TM and JCT regions, whereas TSP-2 predominates in the uveal meshwork. 121 In one study, TSP-1 exhibited more intense immunoreactivity in one-third of patients with POAG, 152 making it of particular interest. Of note, both TGF-b1 and TGF-b2 upregulate TSP-1 in human TM cells, [152][153][154] and treatment with TGF-b2 treatment generally favors ECM accumulation and an increase in resistance to aqueous outflow.…”

Section: Figmentioning

confidence: 99%

“…121 In one study, TSP-1 exhibited more intense immunoreactivity in one-third of patients with POAG, 152 making it of particular interest. Of note, both TGF-b1 and TGF-b2 upregulate TSP-1 in human TM cells, [152][153][154] and treatment with TGF-b2 treatment generally favors ECM accumulation and an increase in resistance to aqueous outflow. 153,[155][156][157][158] Furthermore, TSP-1-like SPARC-may play a role in TM cellular tone, as it has been shown to be antagonized by the actin cytoskeletal disruptor latrunculin A.…”

Section: Figmentioning

confidence: 99%

Matricellular Proteins in the Trabecular Meshwork: Review and Update

Chatterjee

Villarreal

Rhee

2014

Journal of Ocular Pharmacology and Therapeutics

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Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, and intraocular pressure (IOP) is an important modifiable risk factor. IOP is a function of aqueous humor production and aqueous humor outflow, and it is thought that prolonged IOP elevation leads to optic nerve damage over time. Within the trabecular meshwork (TM), the eye's primary drainage system for aqueous humor, matricellular proteins generally allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix (ECM). It is now well established that ECM turnover in the TM affects outflow facility, and matricellular proteins are emerging as significant players in IOP regulation. The formalized study of matricellular proteins in TM has gained increased attention. Secreted protein acidic and rich in cysteine (SPARC), myocilin, connective tissue growth factor (CTGF), and thrombospondin-1 and -2 (TSP-1 and -2) have been localized to the TM, and a growing body of evidence suggests that these matricellular proteins play an important role in IOP regulation and possibly the pathophysiology of POAG. As evidence continues to emerge, these proteins are now seen as potential therapeutic targets. Further study is warranted to assess their utility in treating glaucoma in humans.

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Thrombospondin-1 in the trabecular meshwork: localization in normal and glaucomatous eyes, and induction by TGF-β1 and dexamethasone in vitro

Cited by 114 publications

References 60 publications

Thrombospondin-1 (TSP1)–Null and TSP2-Null Mice Exhibit Lower Intraocular Pressures

Thrombospondin-1 (TSP1)–Null and TSP2-Null Mice Exhibit Lower Intraocular Pressures

Extracellular matrix in the trabecular meshwork

Matricellular Proteins in the Trabecular Meshwork: Review and Update

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