Over-expression of a gelatinase a activity in keratoconus

Smith, Valerie; Hoh, H B; Littleton, M; Easty, D L

doi:10.1038/eye.1995.100

Cited by 56 publications

(46 citation statements)

References 18 publications

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“…However, ongoing release of small amounts of these degradative enzymes over an extended period of time could result in tissue damage. Several studies have detected degradative enzymes and other components at increased levels in keratoconus corneas (Kao et al, 1982 ;Sawaguchi et al, 1989 ;Fini et al, 1992 ;Fukuchi et al, 1994 ;Kenny et al, 1994 ;Smith et al, 1995). Chronic apoptosis could be the factor that links together these observations of increased levels of differing degradative components produced by keratocytes.…”

Section: Discussionmentioning

confidence: 99%

Keratocyte Apoptosis Associated with Keratoconus

Kim

Rabinowitz

Meisler

et al. 1999

Experimental Eye Research

232

138

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Keratoconus is an ectatic corneal dystrophy associated with stromal thinning and disruption of Bowman's layer. The purpose of this study was to explore a possible association between keratocyte apoptosis and keratoconus. Keratocyte apoptosis was evaluated in corneas of patients with keratoconus, corneas of patients with stromal dystrophies, and normal donor corneas using the transferase-mediated dUTP-digoxigenin nick and labeling (TUNEL) assay. Keratocyte apoptosis was also studied in keratoconus and normal corneas using transmission electron microscopy. TUNEL-stained keratocytes were detected in 60 % of corneas with keratoconus, but only 35 % of corneas with stromal dystrophies (P l 0n03). The number of TUNEL-positive keratocytes detected in the keratoconus, stromal dystrophy, and normal corneas was 7p1 (meanpstandard error, range 0-20), 2p0n8 (range 0-9), and 0p0 (range 0-0) TUNEL-positive cells per section, respectively. The differences between the keratoconus and the stromal dystrophy (P l 0n0097) or the normal cornea (P l 0n01) groups were statistically significant. The difference between the stromal dystrophy and normal cornea groups was not statistically significant (P l 0n45). The stromal dystrophy group was included to account for surgery-associated keratocyte apoptosis. No TUNEL-stained keratocytes were detected in normal corneas. Cell morphologic changes consistent with apoptosis were detected by transmission electron microscopy (TEM) in keratocytes of keratoconus corneas, but not in keratocytes in normal corneas. Chronic keratocyte apoptosis associated with ongoing epithelial injury may link risk factors associated with keratoconus such as chronic eye rubbing, contact lens wear, or atopic eye disease. Similarly, increases that have been detected in several different degradative enzymes in keratoconus corneas could be associated with chronic keratocyte apoptosis and less than perfect control of release of intracellular contents.# 1999 Academic Press

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Section: Discussionmentioning

confidence: 99%

Keratocyte Apoptosis Associated with Keratoconus

Kim

Rabinowitz

Meisler

et al. 1999

Experimental Eye Research

232

138

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“…22,106 Another factor could be enhanced MMP-2 activity through overproduction of this protein, whose proenzyme (proMMP-2) is overexpressed in keratoconic corneas. [126][127][128] Production of MMPs is regulated by IL; IL-1, IL-6, IL-7, and TNF-α increase MMP-1, MMP-3, MMP-9, and MMP-13, whereas IL-10 diminishes cathepsins. The enzymatic activity is a result of the balance with its inhibitors (tissue inhibitor of MMP (TIMP)); therefore, its function may increase not only because of a higher IL level but also because of lower level of inhibitors.…”

Section: Enzymatic Imbalancementioning

confidence: 99%

Keratoconus: an inflammatory disorder?

Galvis

Sherwin

Tello

et al. 2015

Eye

303

199

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Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.

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“…The major protease found in corneal stromal tissue is inactive matrix metalloproteinase 2 or proMMP-2 [9,10]. It is known to become activated in the culture medium of metabolically stressed corneal keratocyte cultures [11], and, when activated, will cleave type IV collagen, the major component of basement membranes and type VI collagen, a component of the anchoring fibrils [12].…”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinase 2 Activation in Cultured Corneas

Smith¹,

El-Rakhawy²,

Easty³

2000

Ophthalmic Res

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Purpose: Corneas that are maintained in tissue culture medium shed their epithelial cells and repopulation following graft surgery is an essential facet of the healing process. Failure to do so may be a result of structural damage to the epithelial basement membrane of a donor cornea. The purpose of the present investigation was to ascertain whether MMP-2, the matrix metalloproteinase produced by corneal keratocytes, may be activated during storage and hence cleave the type IV collagen component of the epithelial cell basement membrane. Methods: Fresh and transplant rejected corneas that had been stored in culture medium for varying time periods and of known donor age were collected. The soluble protein fractions of these corneas were obtained. Their MMP-2 proteins were visualised by zymography on SDS gelatin polyacrylamide gels and assayed for activity against nitrophenyl acetate and denatured [³H]type I collagen. Results: The stromal tissue of fresh, normal corneas produced inactive MMP-2 of M_r 66,000. Although the cultured corneas did not up-regulate MMP-2 production, they contained additional MMP-2 activities of M_r 62,000 and M_r 43,000. The appearance of these additional MMP-2 activities correlated with corneal culture time but not donor age. The ability to cleave denatured [³H]type I collagen correlated with the appearance of the M_r 43,000 activity but not the M_r 62,000 activity. Conclusion: Activated MMP-2 is produced in cultured corneas. For this reason the corneas donated for all graft procedures should not be held in culture medium for periods exceeding 4 weeks.

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Over-expression of a gelatinase a activity in keratoconus

Cited by 56 publications

References 18 publications

Keratocyte Apoptosis Associated with Keratoconus

Keratocyte Apoptosis Associated with Keratoconus

Keratoconus: an inflammatory disorder?

Matrix Metalloproteinase 2 Activation in Cultured Corneas

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