,
Voici un article sur les multiples causes du kératocones.
C'est très compliqué et en anglais 
. Avis aux amateurs (j'en connais au moins deux...) 
The Cascade Hypothesis of Keratoconus
M. Cristina Kenney, and Donald J. Brown
Department of Ophthalmology, UCI Medical Center, University of California, Irvine, Building 55, Room 220, 101 The City Drive, Orange CA 92868, USA
Available online 25 May 2003.
Abstract
Keratoconus, a non-inflammatory thinning of the cornea, is a leading indication for corneal transplantation. For its causation, we propose a "Cascade Hypothesis" stating that keratoconus corneas have abnormal or defective enzymes in the lipid peroxidation and/or nitric oxide pathways leading to oxidative damage. The accumulation of oxidative, cytotoxic by-products causes an alteration of various corneal proteins, triggering a cascade of events, (i.e. apoptosis, altered signaling pathways, increased enzyme activities, fibrosis). This hypothesis is supported by biochemical, immunohistochemical and molecular data presented in this review. Based upon this evidence, one can speculate that keratoconus patients should minimize their exposure to oxidative stress. Protective steps should include wearing ultraviolet (UV) protection (in the contact lenses and/or sunglasses), minimizing the mechanical trauma (eye rubbing, poorly fit contact lenses) and keeping eyes comfortable with artificial tears, non-steroidal anti-inflammatory drugs and/or allergy medications.
Author Keywords: Keratoconus; TIMP; Peroxynitrite; Oxidative stress
Article Outline
1. Introduction
2. Genetics of keratoconus
3. Characterization of the abnormal matrix
4. Enzyme and inhibitor abnormalities
5. Apoptosis in keratoconus corneas
6. Abnormal regulation and signal transduction
7. Oxidative damage in keratoconus corneas
8. Future studies for keratoconus research
Acknowledgements
References
1. Introduction
Keratoconus is a continuing clinical problem and a leading indication for corneal transplantation [1, 2, 3 and 4]. Major advances in the treatment of keratoconus include improved technology in rigid gas permeable and hybrid contact lenses and corneal transplantation. For decades there were few advancements related to the pathophysiology of keratoconus. More recently with the development of molecular techniques, there have been great strides in understanding the abnormalities occurring in keratoconus corneas. The advancements accomplished during the past 20 years will be reviewed below.
2. Genetics of keratoconus
The reported incidence of keratoconus is 1 in 2000 individuals [5 and 6]. With the advent of corneal topography and identification of early keratoconus, the apparent prevalence may increase. Watching early keratoconus develop by corneal topography in otherwise "normal-looking" eyes reinforces the complexities of genetic analysis since one can never be sure that a family member does not harbor the disease at the time of evaluation.
Keratoconus has been reportedly associated with other syndromes. For examples, keratoconus is found in 0.5–15% of patients with Trisomy 21 (Down syndrome) [7, 8 and 9], and has been reported in patients with Leber’s congenital amaurosis [10, 11, 12 and 13], Ehlers-Danlos syndrome [14 and 15] and osteogenesis imperfecta [16, 17 and 18].
It is suspected that keratoconus has both genetic and environmental components [6]. This disease is found in identical twins and in many families with two or more generations [19, 20, 21, 22, 23 and 24]. The prevalence of keratoconus in first degree relatives is 3.34%, which is 15–67 times higher than the general population [25]. To date several collagen genes have been excluded as a defect in keratoconus [5]. One study reported in a single, large family the linkage between keratoconus and chromosome 21 [26]. Other investigators showed a genetic linkage on chromosome 17 in patients with Leber’s congenital amaurosis and keratoconus [13]. An abnormality on chromosome 13 has also been associated with keratoconus [27]. In future studies the experimental approaches to identify genetic abnormalities will include analysis of candidate genes and genomic scans using random genetic markers to identify regions of linkage.
Most families with keratoconus show autosomal dominant inheritance with variable penetration [5 and 6]. However, the mouse model for hereditary keratoconus, reportedly is autosomal recessive, androgen dependent and linked to a histocompatability region on chromosome 17 [28]. In the Japanese population, there are three human major histocompatibility complex (HLA) antigens, HLA-A26, B40 and DR9, that are associated with early onset keratoconus [29].
The occurrence of keratoconus and granular corneal dystrophy within the same cornea has been documented histologically [30 and 31]. Mutations in the BIGH3 gene (beta transforming growth factor-induced gene, chromosome 5) are associated with types I–III granular corneal dystrophy (see [32] for review) but screening for similar mutations in keratoconus patients has been negative (Udar et al., personal communication). Keratoconus has been associated with other corneal disorders [5] but these are rare and may be only coincidence.
There are considerable variations among keratoconus patients. For example, keratoconus can be familial (occurring in more than one family member) or sporadic (in an individual only), unilateral or bilateral, involving the central cornea or the inferior cornea. Under these circumstances, it is very likely that keratoconus has multiple gene defects and not just a single gene defect. Future investigations will undoubtedly reveal the genetic associations in keratoconus.
3. Characterization of the abnormal matrix
Early biochemical studies contained unreliable information because poor sensitivity of the methods required the analysis of several corneas that had been pooled together. Our laboratory pioneered micro-methodology for corneal tissue which has allowed us and others to study one diseased cornea at a time.
For years practitioners, contact lens specialists and surgeons noted that unlike other thinned corneas, keratoconus corneas exhibited unusual softness and pliability. Even in the early 1980s, it still was not clear what the basic biochemical abnormalities were in keratoconus corneas. It led researchers to examine collagen crosslinking, total protein, collagen types, and proteoglycan content. Studies found total protein was decreased, the collagen crosslinking was normal, the total collagen content was variable [33 and 34] and the levels of sulfated proteoglycans were decreased [35 and 36]. However, many of these changes were consistent with general wound healing and were not specific for keratoconus.
Recently, with the availability of a variety of specific antibodies, keratoconus corneas were compared to normal corneas and other diseased corneas (Fig. 1). The keratoconus corneas had decreased levels of fibronectin, laminin, entactin, type IV collagen and type XII collagen associated with the epithelial basement membranes [37, 38 and 39]. There were also increased levels of fibrosis-associated extracellular matrices such as type III collagen, tenascin-C, and fibrillin-1 in the regions of anterior stromal scars and disrupted Bowman’s layer [37, 38 and 40]. Many of these extracellular matrix changes were not keratoconus specific but related to general scarring since similar matrix changes were also found in subepithelial fibrosis and scarred regions of bullous keratopathy and failed graft corneas [37 and 40]. Recently, it was reported that keratocan is up-regulated at both the RNA and protein levels compared to normal corneas or other diseases [41].
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Fig. 1. Schematic of extracellular matrix changes and abnormal enzymes/inhibitors in a keratoconus cornea. (A) Disrupted Bowman’s layer has decreased levels of fibronectin, laminin, entactin and type IV collagen. (B) Subepithelial fibrosis has increased levels of tenascin-C, type III collagen and fibrillin-1. (C) Stromal thinning is a result of increased enzyme activities (gelatinase and lysosomal enzymes) and decreased enzyme inhibitors (TIMP-1, -1 proteinase inhibitor and 2-macroglobulin). Epi, epithelium; Str, stroma; Endo, endothelium.
In summary, within a single keratoconus cornea, the abnormalities are not uniform. There are areas where basement membrane components are absent, reflecting regions of increased proteolytic activities. In other areas there are deposits of fibrotic matrix components but in general these are not keratoconus specific since they are also found in wound healing and other diseases.
4. Enzyme and inhibitor abnormalities
In the early 1980s different laboratories reported that keratoconus corneas had elevated levels of gelatinase activity [42, 43 and 44]. Later studies reported that keratoconus corneas had increased lysosomal enzymes such as acid esterase, acid phosphatase and acid lipases [45, 46 and 47].
While lysosomal enzymes might posses some gelatinase activity [45 and 46], we, and others, pointed out that another gelatinolytic enzyme, the matrix metalloproteinase-2 (MMP-2), probably also has a role in keratoconus [48, 49, 50, 51 and 52]. It is likely that keratoconus corneas have an imbalance between the corneal MMP-2 and its inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Keratoconus corneas have decreased levels of TIMP-1 [53], and after chemical inactivation of the TIMPs, the keratoconus corneas have greater gelatinase activity compared to normal corneas [48, 50, 51 and 52]. More recently, Collier et al. showed that MT1-MMP (MMP-14), the membrane-type metalloproteinase that activates MMP-2, is elevated in keratoconus corneas [54]. The role that MMPs play in keratoconus is still not resolved and is an area for future studies [55].
What is the role of the inhibitors of these destructive enzymes in keratoconus? To date, investigations show that three different enzyme inhibitors are decreased in keratoconus corneas, the 1-proteinase inhibitor, 2-macroglobulin and TIMP-1 [46, 53 and 56]. The decreased levels of these inhibitors are associated with increased activities of the degradative enzymes [48, 51 and 57]. The 1-proteinase inhibitor is capable of blocking trypsin, chymotrypsin, elastase and plasmin; the 2-macroglobulin blocks trypsin, chymotrypsin, papain, collagenase, elastase, thrombin, plasmin and kallikrein; the TIMP-1 inhibits matrix metalloproteinases but also can inhibit apoptosis [58 and 59] and affect cell growth [60 and 61]. One mechanism by which the keratoconus corneas have decreased TIMP-1 levels may be related to the presence of peroxynitrite, a cytotoxic by-product of the nitric oxide pathway [62]. Recent in vitro studies show that by-products of oxidative stress can degrade TIMP-1 protein [53 and 63].
In summary, the keratoconus corneas have decreased levels of enzyme inhibitors and increased enzyme activities that can degrade the various extracellular matrices within the keratoconus corneas. The inhibitor–enzyme imbalance undoubtedly plays a major role in the stromal thinning and Bowman’s layer/basement membrane breaks that are characteristic of keratoconus corneas (Fig. 1). In addition, the decreased level of at least one of these inhibitors, TIMP-1, may also play a role in the apoptosis and/or the altered cell behavior found in keratoconus.
5. Apoptosis in keratoconus corneas
Apoptosis is the programmed cell death that occurs in development, diseases and wound healing [64, 65 and 66]. In addition, apoptosis is important in the normal cellular turn over of many healthy tissues.
A major finding related to keratoconus is that apoptosis occurs in the anterior stroma [67] and other layers of the cornea [68] ( Fig. 2). Animal studies also show that chronic, repetitive removal of the corneal epithelium can stimulate stromal apoptosis [69 and 70]. This is significant because keratoconus corneas are likely to have chronic irritation due to the use of rigid gas permeable contact lenses, vigorous eye rubbing and moderate to severe atopy. Wilson suggests that mechanical trauma to the epithelium may cause the apoptosis in the underlying stromal cells of keratoconus corneas [70 and 71]. We have described two other mechanisms by which apoptosis might occur. There is an increased level of leukocyte common antigen related protein (LAR) that is present in keratoconus corneas but not in normal corneas [72]. LAR, a transmembrane phosphotyrosine phosphatase, can stimulate apoptosis [73, 74, 75, 76 and 77]. A third possible mechanism is that apoptosis is inhibited by TIMP-1 [58 and 59] and keratoconus corneas have decreased levels of TIMP-1 [53].
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Fig. 2. Schematic of keratoconus cornea with apoptosis of anterior stromal cells. (A) Apoptotic cells with condensed nuclear material. Epi, epithelium; Str, stroma; Endo, endothelium.
In summary, the keratoconus corneas have increased apoptosis and this phenomenon of cell death may be important in its pathogenesis. Factors that cause apoptosis include chronic epithelial cell damage, increased levels of LAR and decreased levels of TIMP-1. Wilson suggests that apoptosis may be the prime causative mechanism at work in keratoconus corneas but we feel that it is probably only one of several pathways in the cascade of events causing keratoconus.
6. Abnormal regulation and signal transduction
What is the role of abnormalities of subcellular regulation and signal transduction? The expression of specific genes is regulated by transcription factors. One of these transcription factors, Sp1, is elevated in keratoconus corneas [78]. Further studies showed that the Sp1 could repress the promoter activity of the 1-proteinase inhibitor and therefore lead to decreased levels of this inhibitor in vitro [79]. The 1-proteinase inhibitor is decreased in keratoconus corneas [56]. However, the abnormal levels of Sp1 are probably not the entire story because other lysosomal enzymes and inhibitors that are altered in keratoconus corneas are not regulated by the Sp1 transcription factor [57].
Differential display analysis of corneal genes, a technique pioneered in our laboratory, demonstrated a phosphotyrosine phosphatase enzyme (LAR) that was found in keratoconus but lacking in normal corneas or other diseased corneas [72]. The function of the phosphotyrosine phosphatase(s) is removal of the phosphates from the tyrosine molecules [80]. This dephosphorylation of tyrosine is the mechanism by which LAR affects intracellular signaling [81, 82 and 83], cell-matrix interactions [83 and 84] and induction of apoptosis [73 and 74].
In summary, keratoconus corneas have increased levels of Sp1, a transcription factor that can down-regulate 1-proteinase inhibitor. The keratoconus corneas also have abnormalities in the tyrosine phosphatase (LAR) signal transduction pathways. These data suggest that multiple cellular pathways are abnormal in keratoconus corneas. How these pathways are inter-related is not clear but investigations are underway to find a "common denominator" that can tie them together.
7. Oxidative damage in keratoconus corneas
We propose a working hypothesis that could unify most of the disparate facts known about keratoconus. This "Cascade Hypothesis" states that keratoconus corneas have underlying defects in their ability to process reactive oxygen species and thereby undergo oxidative damage. This triggers a series of "downstream" events that ultimately leads to corneal thinning and loss of vision.
Supporting evidence is that keratoconus corneas accumulate large amounts of cytotoxic by-products from both the lipid peroxidation and nitric oxide pathways [62 and 85]. Keratoconus corneas also have reduced levels of aldehyde dehydrogenase Class 3 (ALDH3), an important corneal enzyme responsible for elimination of reactive aldehydes of the lipid peroxidation pathway [86 and 87]. Others report that keratoconus corneas also have reduced levels of superoxide dismutase [88 and 89]. The corneal superoxide dismutase is an important antioxidant enzyme responsible for elimination of reactive oxygen species such as free radicals or superoxides ( Fig. 3) [88]. Abnormalities of another antioxidant enzyme (catalase) has been confirmed at the molecular level (unpublished data). Taken together, the keratoconus corneas are deficient in at least two or more critical enzymes (ALDH3, superoxide dismutase, and catalase) whose functions are to remove reactive oxygen species and reactive aldehydes. As a result, we have shown that keratoconus corneas have significantly increased accumulation of malondialdehyde (MDA), a cytotoxic aldehyde from the lipid peroxidation pathway and nitrotyrosine (NT), representing peroxynitrite, a cytotoxic by-product of the nitric oxide pathway ( Fig. 4 and Fig. 5) [62 and 85].
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Fig. 3. Diagram of the sequence of events that leads to oxidative damage.
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Fig. 4. Diagram of the consequences related to the accumulation of peroxynitrite/nitrotyrosine within the keratoconus corneas. TIMP-1, tissue inhibitor of metalloproteinase 1.
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Fig. 5. Diagram of the consequences related to the accumulation of cytotoxic aldehydes/MDA within the keratoconus corneas.
The consequence of the accumulation of nitrotyrosine (peroxynitrite) within the keratoconus cornea is that various proteins can undergo nitration, become fragmented and altered their functions (Fig. 4). In vitro studies show that in the presence of a peroxynitrite donor, TIMP-1 is degraded and cultures have increased gelatinolytic activity [53].
In terms of the lipid peroxidation pathway, the consequence of the accumulation of MDA in the keratoconus corneas could be the release of lysosomal enzymes (Fig. 5). It has been demonstrated that reactive aldehydes from the lipid peroxidation pathway can disrupt the membranes of lysosomes resulting in the release of the enzyme contents [90, 91 and 92]. In other words, the presence of cytotoxic by-products (peroxynitrite and/or MDA) can result in altered protein functions leading to a cascade of events, including apoptosis, increased enzyme activities, etc.
In summary, keratoconus corneas have increased oxidative damage compared to normal or other corneal diseases. They lack the necessary enzyme components (ALDH3, superoxide dismutase) to process the reactive oxygen species that occur. With an accumulation of the reactive oxygen species, there is a resultant deposition of cytotoxic by-products (MDA and peroxynitrites) that can damage the corneal tissues. Therefore with our keratoconus patients it may be prudent to minimize the traumas and insults to their corneas. Sources of reactive oxygen species include ultraviolet light (UV), mechanical trauma (vigorous eye rubbing, poorly fit contact lenses) and atopy/allergies. Interestingly, this exposure of the interpalpebral fissure area to UV light and oxidative stress might be an explanation for the propensity of keratoconus to develop in the "exposure" area of the cornea.
What practical information can we use as practitioners from the Cascade Hypothesis and its inclusion of the new information about the susceptibility of keratoconus corneas to oxidative stress? Perhaps it is time to recommend UV protection in the contact lenses and sunglasses used by our keratoconus patients (Table 1). Efforts should be made to improve patient comfort in order to minimize the eye rubbing. Perhaps, patients should by encouraged to use non-steroidal anti-inflammatory medications (NSAIDs), copious preservative-free artificial tears and/or allergy medications. While the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study has explored many aspects of the natural history of keratoconus [93] and continues to investigate the fitting of contact lenses in these patients, we, as eye-care practitioners, should make a concerted effort to minimize trauma to the corneas of our keratoconus patients.
Table 1. Recommendation for keratoconus patients
8. Future studies for keratoconus research
Biochemical and/or genetic identification of different types of keratoconus might allow us to classify patients early as to mild, non or slowly progressive versus the more severe forms. It might also allow use of gene therapy or other approaches such as topical cross-linkers.
Future studies should focus on further clarification of the mechanism and/or defect(s) related to the oxidative stress in keratoconus corneas. We also need to identify the genetic and environmental factors associated with keratoconus. Finally an area for future investigations will be developing therapeutic interventions which can block the cascade of molecular events occurring in this disease.
Addendum
As this manuscript was being published, and article came out that described linkage to 16q22.3–q23.1 for autosomal dominant keratoconus [94].
Acknowledgements
Supported by NIH EY06807, the Schoellerman Charitable Foundation, the Discovery Fund for Eye Research, the Skirball Molecular Ophthalmology Program, and the National Keratoconus Foundation.
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