Hypophosphorylation of Aqueous Humor sCD44 and Primary Open-Angle Glaucoma

Knepper, Paul A.; Miller, Adam; Choi, John Y.; Wertz, Robert D.; Nolan, Michael; Goossens, William; Whitmer, Susan; Yue, Beatrice Y.J.T.; Ritch, Robert; Liebmann, Jeffrey M.; Allingham, R Rand; Samples, John R.

doi:10.1167/iovs.04-1472

Cited by 41 publications

(33 citation statements)

References 41 publications

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“…(Xue et al 2006;Xue et al 2007) Increases in soluble CD44, particularly the phosphorylated form, have also been recently linked to glaucoma, although causal relationships remain to be established. (Knepper, PA et al 1998;Knepper, P et al 2002;Knepper, PA et al 2002;Knepper et al 2005) In an extension of the GAG stratification within the JCT region, discussed earlier, large changes in GAG distributions have also been observed in glaucoma. HA was decreased and CS was increased in all layers of the JCT of primary open-angle glaucoma eyes.…”

Section: Glaucoma and Ecmmentioning

confidence: 94%

“…( Another cell-surface ECM receptor, CD44, which is a hyaluronan receptor, has been studied in the TM in some detail and clearly plays an important role, directly or indirectly, in outflow and TM function. (Knepper, P et al 1998;Knepper, P et al 2002;Choi et al 2005;Knepper et al 2005) An important impact of the truncated soluble form of CD44 on TM cells has been reported. Alternative mRNA splicing of CD44 in the TM is also observed.…”

Section: Cell-surface Ecm Receptors Of the Tmmentioning

confidence: 99%

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Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

425

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: Glaucoma and Ecmmentioning

confidence: 94%

Section: Cell-surface Ecm Receptors Of the Tmmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

425

443

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“…Their results indicate that CD44H may represent a marker of POAG and an etiologic factor in the POAG disease process. The ectodomain of CD44 is shed as a 32 kDa fragment-soluble CD44 (sCD44) which is cytotoxic to TM cells and retinal ganglion cells in culture (57) . It has been shown that sCD44 adversely affects retinal ganglion cells and TM cell survival in vitro, by activating a proapoptotic pathway (58) .…”

Section: Cd44hmentioning

confidence: 99%

Biomarkers in primary open angle glaucoma

Kokotas

Kroupis

Chiras

et al. 2012

Clinical Chemistry and Laboratory Medicine (CCLM)

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Glaucoma, a leading cause of blindness worldwide, is currently defi ned as a disturbance of the structural or functional integrity of the optic nerve that causes characteristic atrophic changes in the optic nerve, which may lead to specifi c visual fi eld defects over time. This disturbance usually can be arrested or diminished by adequate lowering of intraocular pressure (IOP). Glaucoma can be divided roughly into two main categories, ' open angle ' and ' closed angle ' glaucoma. Open angle, chronic glaucoma tends to progress at a slower rate and patients may not notice loss of vision until the disease has progressed signifi cantly. Primary open angle glaucoma (POAG) is described distinctly as a multifactorial optic neuropathy that is chronic and progressive with a characteristic acquired loss of optic nerve fi bers. Such loss develops in the presence of open anterior chamber angles, characteristic visual fi eld abnormalities, and IOP that is too high for the healthy eye. It manifests by cupping and atrophy of the optic disc, in the absence of other known causes of glaucomatous disease. Several biological markers have been implicated with the disease. The purpose of this study was to summarize the current knowledge regarding the non-genetic molecular markers which have been predicted to have an association with POAG but have not yet been validated.

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“…5 A hypo-phosphorylated form of sCD44 in POAG aqueous humor further distinguishes POAG and normal pressure glaucoma from normal eyes and other types of glaucoma. 19 Moreover, sCD44, particularly the hypo-phosphorylated form of sCD44, is a potent and specific cytotoxin to trabecular meshwork (TM) and retinal ganglion cells. 4 CD44 is a member of a heterogeneous group of proteins designated hyaladherins, which are linked by their common ability to bind to hyaluronic acid (HA).…”

Section: Methodsmentioning

confidence: 99%

sCD44 Internalization in Human Trabecular Meshwork Cells

Nolan

Koga

Walker

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine whether soluble CD44 (sCD44), a likely biomarker of primary open-angle glaucoma (POAG), is internalized in cultured human trabecular meshwork (TM) cells and trafficked to mitochondria. METHODS.In vitro, 32-kD sCD44 was isolated from human sera, biotinylated, and dephosphorylated. TM cells were incubated for 1 hour at 48C with biotinylated albumin (b-albumin), biotinlabeled sCD44 (b-sCD44), or hypophosphorylated biotinlabeled sCD44 (-p b-sCD44) in the presence or absence of unlabeled sCD44, hyaluronic acid (HA), and a selected 10-mer HA binding peptide. The slides were warmed for 1 or 2 hours at 378C, and 125 nM MitoTracker Red was added for the last 20 minutes of the incubation. The cells were washed, fixed, incubated with anti-biotin antibody and FITC-labeled goat antimouse antibody, and examined under a confocal microscope.RESULTS. TM cell membranes were positive for b-sCD44 after 48C incubation. When the temperature was raised to 378C, bsCD44 or -p b-sCD44 appeared in the cytoplasm. The internalization of b-sCD44 was blocked by excess unlabeled sCD44, HA, and a 10-mer HA-binding peptide. Double label experiments with b-sCD44 or -p b-sCD44 and MitoTracker Red indicated partial overlap. The percent co-localization of MitoTracker Red at 2 hours and FITC -p b-sCD44 was 17.4% (P < 0.001) and for FITC b-sCD44 was 11.7% (P < 0.001) compared with b-albumin. The influence of putative CD44 phosphorylation sites on mitochondrial trafficking was determined by TargetP 1.1.CONCLUSIONS. sCD44 is internalized by TM cells and trafficked in part to mitochondria, which may be a factor in the toxicity of sCD44 in the POAG disease process. (Invest Ophthalmol Vis Sci. 2013;54:592-601)

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Hypophosphorylation of Aqueous Humor sCD44 and Primary Open-Angle Glaucoma

Cited by 41 publications

References 41 publications

Extracellular matrix in the trabecular meshwork

Extracellular matrix in the trabecular meshwork

Biomarkers in primary open angle glaucoma

sCD44 Internalization in Human Trabecular Meshwork Cells

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