Materiały źródłowe

• #1 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. […] The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. […] After the onset of KC various environmental effects such as inflammation, degeneration or scarring cause secondary changes that modify the corneal tissue. […] Each step of this process has been examined with regard to the pathogenesis of KC, but as with many complex diseases, distinguishing between association, cause and effect is problematic and extremely challenging. […] Thus, despite a great deal of research, the aetiology of KC is still poorly understood. […] For KC the currently recognised environmental influences include contact lens wear, chronic eye rubbing and allergic eye disease.

• #2 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. […] The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. […] After the onset of KC various environmental effects such as inflammation, degeneration or scarring cause secondary changes that modify the corneal tissue. […] Each step of this process has been examined with regard to the pathogenesis of KC, but as with many complex diseases, distinguishing between association, cause and effect is problematic and extremely challenging. […] Thus, despite a great deal of research, the aetiology of KC is still poorly understood. […] For KC the currently recognised environmental influences include contact lens wear, chronic eye rubbing and allergic eye disease.

• #3 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The reported prevalence of KC is highly variable ranging from 2340 per 100000 in Israel to 0.20.4 per 100000 in Russia. […] Although the majority of cases of KC are sporadic, reports of familial cases of KC are also common and aggregation of the disease in families is often observed. […] The prevalence of KC in first degree relatives of index cases has been estimated to be 3.34%, notably higher than that in the general population. […] Genetic risk factors for KC have proven difficult to identify because of the complex nature of the condition. […] Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC. […] Different approaches have been used to investigate and define the phenotype, mechanisms and causes of KC.

• #4 Pathophysiology of Keratoconus: What Do We Know Today

  https://openophthalmologyjournal.com/VOLUME/11/PAGE/252/FULLTEXT/

  Additionally, evidence for the role of genetics in KC comes from prior evidence of familial aggregation of KC: unaffected relatives of KC patients may have abnormal videokeratography indices. […] The cumulative proteomic findings suggest a generalized loss of the normal quiescent phenotype of the keratocytes and an increase in the abnormal protein expression, similarly to that associated with wound healing phenotype. […] Overall, it appears that KC may be caused by an aberrant tissue response to one or more unidentified stimuli that subsequently leads to keratocyte depletion or dysfunction, loss of collagen, and ultimately a biomechanically weak cornea with a degenerated ECM. […] Despite major leaps in methodology, the origin and pathogenesis of KC remain elusive.

• #5 Pathophysiology of Keratoconus: What Do We Know Today

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5585454/

  Keratoconus is a common corneal ectasia that leads to progressive visual impairment. Numerous studies have shown abnormal protein expression patterns in keratoconic corneas. However, the specific mechanisms causing this disease remain ambiguous. […] The disease process in the cornea results in a myopic shift and irregular astigmatism that may cause significant impairment in visual function and may not be amenable to spectacle correction. […] Specifically, two small nuclear polymorphisms were identified to confer high risk for developing KC: FOXO1 and FNDC3B. FOXO1 acts by regulating the TGF- pathway, which by itself may be implicated in the pathogenesis of KC. […] Additionally, evidence for the role of genetics in KC comes from prior evidence of familial aggregation of KC: unaffected relatives of KC patients may have abnormal videokeratography indices.

• #6 Pathophysiology of Keratoconus: What Do We Know Today

  https://openophthalmologyjournal.com/VOLUME/11/PAGE/252/FULLTEXT/

  Keratoconus is a common corneal ectasia that leads to progressive visual impairment. Numerous studies have shown abnormal protein expression patterns in keratoconic corneas. However, the specific mechanisms causing this disease remain ambiguous. […] The disease process in the cornea results in a myopic shift and irregular astigmatism that may cause significant impairment in visual function and may not be amenable to spectacle correction. […] KC may be an isolated finding or it may be associated with other systemic disorders or syndromes, such as: Down syndrome, Leber congenital amaurosis and connective tissue diseases (for instance: Ehlers Danlos, Marfan syndrome, etc.). […] Specifically, two small nuclear polymorphisms were identified to confer high risk for developing KC: FOXO1 and FNDC3B. FOXO1 acts by regulating the TGF- pathway, which by itself may be implicated in the pathogenesis of KC.

• #7 Pathophysiology of Keratoconus: What Do We Know Today

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5585454/

  Keratoconus is a common corneal ectasia that leads to progressive visual impairment. Numerous studies have shown abnormal protein expression patterns in keratoconic corneas. However, the specific mechanisms causing this disease remain ambiguous. […] The disease process in the cornea results in a myopic shift and irregular astigmatism that may cause significant impairment in visual function and may not be amenable to spectacle correction. […] Specifically, two small nuclear polymorphisms were identified to confer high risk for developing KC: FOXO1 and FNDC3B. FOXO1 acts by regulating the TGF- pathway, which by itself may be implicated in the pathogenesis of KC. […] Additionally, evidence for the role of genetics in KC comes from prior evidence of familial aggregation of KC: unaffected relatives of KC patients may have abnormal videokeratography indices.

• #8 Beyond The Cornea: The Complex Interplay of Genetics and Environment in Keratoconus – Vision Science Academy

  https://visionscienceacademy.org/beyond-the-cornea-the-complex-interplay-of-genetics-and-environment-in-keratoconus/

  Keratoconus pathogenesis is influenced by both hereditary and environmental factors. […] Keratoconus is caused by a complex mix of environmental and genetic factors. Eye rubbing, atopy, and UV exposure are all environmental variables. Excessive levels of any of the components induce oxidative damage to keratoconus corneas due to the inability of keratoconus to handle reactive oxygen species, resulting in a degradation process that results in corneal thinning and vision loss. […] Keratoconus pathogenesis is heavily influenced by genetics. Some of the origins of genetics include familial inheritance, discordance between dizygotic twins, and other recognized genetic abnormalities. […] In keratoconus-affected corneas, a buildup of cytotoxic byproducts breaks mitochondrial DNA and causes high levels of oxidative stress. The involvement of VSX1 (visual system homeobox 1) and SOD1 (superoxide dismutase 1) in the development of keratoconus is influenced by genetic variables. The most prevalent family keratoconus pattern is autosomal dominant and sporadic. […] Both environmental and genetic factors contribute to the pathogenesis of keratoconus, with eye rubbing being the most important risk factor, followed by allergies and sun exposure.

• #9

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Shetty et al. (2015) studied the expression of select genes associated with corneal structure in a large cohort of patients with keratoconus (90 eyes) compared with patients undergoing photorefractive keratectomy who did not have keratoconus (52 eyes). Shetty et al. (2015) observed a significant reduction in lysyl oxidase (LOX; 153455) transcript levels in KTCN corneal epithelia, and LOX activity in KCTN tears correlated with disease severity. Collagen transcript levels (COL1A1, 120150; COL4A1, 120130) were also reduced in KCTN, whereas MMP9 (120361) transcript levels were upregulated and correlated with disease severity. IL6 (147620) transcript levels were moderately increased in KCTN patients. Immunohistochemistry demonstrated a reduction in the protein expression levels of LOX in the epithelium and COL4A1 in the basement membrane of KCTN patients (27 eyes) compared to healthy donor corneas (15 eyes). Shetty et al. (2015) concluded that the structural deformity of the KCTN cornea may be dependent on reduced expression of collagens and LOX, as well as on the concomitant increased expression of MMP9.

• #10

  https://abp.ptbioch.edu.pl/index.php/abp/article/view/1923

  Keratoconus (KC) is a corneal disease associated with structural abnormalities in the corneal epithelium, Bowman’s layer and stroma and altered concentration of tear components. […] Altered expression and/or activity of lysyl oxidase, a critical enzyme of the biogenesis of connective tissue detected in KC corneas, may weaken covalent bonds between collagen and elastin fibrils, what may lead to biomechanical deterioration of the cornea. Increased activity of matrix metalloproteinases observed in KC may induce the degradation of the extracellular matrix causing damage to the cornea. […] Oxidative and nitrative stress play an important role in KC pathogenesis and KC corneas are characterized by the disturbed lipid peroxidation and nitric oxide pathways. Malfunctioning of these pathways may lead to accumulation of their toxic by-products inducing several detrimental effects, along with apoptosis of the corneal cells, which may result from the loss of -actin or increased levels of cytokines, including interleukin-1 and -6. Change in the expression of genes associated with wound healing, including the nerve growth factor and the visual system homeobox 1, may contribute to increased susceptibility of KC corneas to injury. Consequently, biochemical changes may play an important role in KC pathophysiology and, therefore, can be considered in prevention, diagnosis, prognosis and in the therapy of this disease as well.

• #11

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Shetty et al. (2015) studied the expression of select genes associated with corneal structure in a large cohort of patients with keratoconus (90 eyes) compared with patients undergoing photorefractive keratectomy who did not have keratoconus (52 eyes). Shetty et al. (2015) observed a significant reduction in lysyl oxidase (LOX; 153455) transcript levels in KTCN corneal epithelia, and LOX activity in KCTN tears correlated with disease severity. Collagen transcript levels (COL1A1, 120150; COL4A1, 120130) were also reduced in KCTN, whereas MMP9 (120361) transcript levels were upregulated and correlated with disease severity. IL6 (147620) transcript levels were moderately increased in KCTN patients. Immunohistochemistry demonstrated a reduction in the protein expression levels of LOX in the epithelium and COL4A1 in the basement membrane of KCTN patients (27 eyes) compared to healthy donor corneas (15 eyes). Shetty et al. (2015) concluded that the structural deformity of the KCTN cornea may be dependent on reduced expression of collagens and LOX, as well as on the concomitant increased expression of MMP9.

• #12 Genetics in Keratoconus: where are we? | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-016-0047-5

  KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. […] Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelialstromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. […] Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. […] Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. […] These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.

• #13 Genetics in Keratoconus: where are we? | Eye and Vision | Full Text

  https://eandv.biomedcentral.com/articles/10.1186/s40662-016-0047-5

  KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. […] Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelialstromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. […] Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. […] Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. […] These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.

• #14 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Genetic risk factors for KC have proven difficult to identify because of the complex nature of the condition. […] Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC. […] Different approaches have been used to investigate and define the phenotype, mechanisms and causes of KC. […] Observations of corneal changes that occur in KC often do not distinguish between primary changes and secondary inflammatory or degenerative effects. […] Although many differences have been identified that distinguish the KC cornea from the normal cornea, it has not been possible to trace these changes back to primary causes, or to identify the triggers that precipitate the cascade of events that leads to the clinical picture of KC. […] Similarly, a range of suggestive genetic loci and variants have been implicated in the genetic susceptibility of KC, however the current lack of large effect contributions of these loci, SNPs and gene variants suggests a complex aetiology or convergence of multiple disease pathways.

• #15 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The reported prevalence of KC is highly variable ranging from 2340 per 100000 in Israel to 0.20.4 per 100000 in Russia. […] Although the majority of cases of KC are sporadic, reports of familial cases of KC are also common and aggregation of the disease in families is often observed. […] The prevalence of KC in first degree relatives of index cases has been estimated to be 3.34%, notably higher than that in the general population. […] Genetic risk factors for KC have proven difficult to identify because of the complex nature of the condition. […] Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC. […] Different approaches have been used to investigate and define the phenotype, mechanisms and causes of KC.

• #16 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. […] The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. […] After the onset of KC various environmental effects such as inflammation, degeneration or scarring cause secondary changes that modify the corneal tissue. […] Each step of this process has been examined with regard to the pathogenesis of KC, but as with many complex diseases, distinguishing between association, cause and effect is problematic and extremely challenging. […] Thus, despite a great deal of research, the aetiology of KC is still poorly understood. […] For KC the currently recognised environmental influences include contact lens wear, chronic eye rubbing and allergic eye disease.

• #17 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. […] The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. […] After the onset of KC various environmental effects such as inflammation, degeneration or scarring cause secondary changes that modify the corneal tissue. […] Each step of this process has been examined with regard to the pathogenesis of KC, but as with many complex diseases, distinguishing between association, cause and effect is problematic and extremely challenging. […] Thus, despite a great deal of research, the aetiology of KC is still poorly understood. […] For KC the currently recognised environmental influences include contact lens wear, chronic eye rubbing and allergic eye disease.

• #18 More to keratoconus than meets the cornea: Be sure to flip the lids

  https://www.ophthalmologytimes.com/view/more-to-keratoconus-than-meets-the-cornea-be-sure-to-flip-the-lids

  Keratoconus is characterized by noninflammatory progressive thinning of the cornea. […] While the precise etiology of keratoconus is unclear, it is suspected to occur from a combination of genetic, environmental, and hormonal influences. […] The authors determined that the most significant risk factor for keratoconus was eye rubbing, reporting that study participants with eye rubbing, regardless of their degree of atopy, were at a 5-7 times higher risk of developing keratoconus. […] Thus, the most likely mechanism by which atopy might contribute to keratoconus is through the eye rubbing tendency of atopic patients. […] The act of eye rubbing then releases inflammatory cytokines, which have been associated with the progression of keratoconus. […] In keratoconus, one study proposed the mechanism that damaged epithelial cells could activate MMP-2 via induced (Membrane type 1) MT1-MMP, causing degradation of the basement membrane; this would lead to cytokine diffusion from the damaged epithelium to the stroma and promote (Interleukin-1) IL-1-mediated inflammation.

• #19 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Despite a plethora of alterations and associations identified with KC, the cause-and-effect relationship remains unclear. […] The single most important etiological association in KC is believed to be eye rubbing, which can be a factor in up to two-thirds of cases. […] Several studies have confirmed this association and the fact that other associations like allergic disease and Down syndrome in turn have eye rubbing as a clinical feature. […] The etiological relationship between KC and CL wear is uncertain. […] Atopy represents an inherent (genetic) predisposition to developing allergic eye disease. […] Many connective tissue disorders have KC as a manifestation of their clinical spectrum of signs, suggesting that the corneal collagen changes leading to KC are a manifestation of systemic disorders of collagen metabolism.

• #20 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Keratoconus is described as a multifactorial condition, implying that many factors contribute to its causation, structural alterations, and progression. […] The most important etiological association in keratoconus is believed to be eye rubbing; pressure on the eye, as seen with floppy eyelid syndrome and some lid and orbital tumors, is also a factor in the etiology of keratoconus. […] Atopic conditions are associated with 30% to 50% of cases of keratoconus and include vernal keratoconjunctivitis, atopic keratoconjunctivitis, atopic dermatitis (eczema), hay fever, and asthma. […] Elastin degradation in the pre-Descemet (Duas) layer has recently been recognized in the pathophysiology of keratoconus. […] The pathogenesis of keratoconus (KC), the commonest ectatic disorder of the cornea, involves all of these except neoplasia.

• #21 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Despite a plethora of alterations and associations identified with KC, the cause-and-effect relationship remains unclear. […] The single most important etiological association in KC is believed to be eye rubbing, which can be a factor in up to two-thirds of cases. […] Several studies have confirmed this association and the fact that other associations like allergic disease and Down syndrome in turn have eye rubbing as a clinical feature. […] The etiological relationship between KC and CL wear is uncertain. […] Atopy represents an inherent (genetic) predisposition to developing allergic eye disease. […] Many connective tissue disorders have KC as a manifestation of their clinical spectrum of signs, suggesting that the corneal collagen changes leading to KC are a manifestation of systemic disorders of collagen metabolism.

• #22 Beyond The Cornea: The Complex Interplay of Genetics and Environment in Keratoconus – Vision Science Academy

  https://visionscienceacademy.org/beyond-the-cornea-the-complex-interplay-of-genetics-and-environment-in-keratoconus/

  Keratoconus pathogenesis is influenced by both hereditary and environmental factors. […] Keratoconus is caused by a complex mix of environmental and genetic factors. Eye rubbing, atopy, and UV exposure are all environmental variables. Excessive levels of any of the components induce oxidative damage to keratoconus corneas due to the inability of keratoconus to handle reactive oxygen species, resulting in a degradation process that results in corneal thinning and vision loss. […] Keratoconus pathogenesis is heavily influenced by genetics. Some of the origins of genetics include familial inheritance, discordance between dizygotic twins, and other recognized genetic abnormalities. […] In keratoconus-affected corneas, a buildup of cytotoxic byproducts breaks mitochondrial DNA and causes high levels of oxidative stress. The involvement of VSX1 (visual system homeobox 1) and SOD1 (superoxide dismutase 1) in the development of keratoconus is influenced by genetic variables. The most prevalent family keratoconus pattern is autosomal dominant and sporadic. […] Both environmental and genetic factors contribute to the pathogenesis of keratoconus, with eye rubbing being the most important risk factor, followed by allergies and sun exposure.

• #23 New Evidence Strengthens the Link Between Air Pollution and Keratoconus

  https://www.reviewofoptometry.com/article/new-evidence-strengthens-the-link-between-air-pollution-and-keratoconus

  A recent study published in Ophthalmic Epidemiology highlights the connection between air pollution and keratoconus, revealing that fine particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) may aggravate the condition. Researchers found that pollution could affect corneal structure directly and stimulate known risk factors such as eye rubbing and atopy. […] The three most implicated factors in the pathogenesis of keratoconus are UV radiation, eye rubbing and atopy. […] This research suggests pollution can affect the cornea both directly and indirectly, they said. The indirect pathway involves the stimulation of recognized risk factors for keratoconus, such as eye rubbing and atopy, they wrote. […] Patients with keratoconus may be more sensitive to the accumulation of reactive oxygen species, associated with air pollution, in the cornea, which could elevate the rate of cell death and contribute to corneal thinning, according to the study authors. This process may induce the development of keratoconus in genetically predisposed individuals and exacerbate its evolution where its already present, they wrote. […] Although further research is needed, this study appears to show that air pollution influences keratoconus development indirectly by stimulating eye rubbing and atopy, and that fine particles may directly affect corneal structures and increase cell apoptosis, the authors concluded.

• #24 Causes – Keratoconus Specialists | Complete Family Eyecare

  https://www.keratoconusmn.com/causes/

  The exact cause of keratoconus remains elusive. Contributing factors seem to include genetic and possible hormonal factors but environmental factors may also play a role in the development of keratoconus. […] Keratoconus is much more common in males than females suggesting a possible hormonal component but an exact mechanism has never been determined. […] From an environmental perspective, there is some degree of correlation but no definitive numbers on the increase risk of keratoconus due to eye rubbing (feels really good but should be discouraged!). Excessive rubbing the eyes may put mechanical pressure on the cornea, further weakening the corneal structure. […] On a cellular level, keratoconus appears to be caused by the loss of Bowman’s layer of the corneal. The cornea is essentially transparent skin tissue and similar to other skin, the cornea is composed of different and distinct layers. Bowman’s layer lies beneath the outermost layer (epithelium) of the cornea and the middle layer of the cornea which is called the stroma. The stroma is the thickest layer of the cornea and is responsible for the majority of its strength and stability. Without the presence of Bowman’s layer, the stromal layer comes in direct contact with the epithelium and this interaction appears to cause the weakening of the stromal collagen and destabilization of the corneal. How this interaction occurs chemically is still another mystery with several theories involving enzymes, free radicals, and chemical inhibitors with gigantically long chemical names which we won’t go into. […] Although the true cause of keratoconus remains a mystery, ongoing research and new studies will hopefully shed some light on the root of this inconvenient condition.

• #25 The role of environment in the pathogenesis of keratoconus: Ingenta Connect

  https://www.ingentaconnect.com/content/wk/icu/2021/00000032/00000004/art00012

  This study was conducted to demonstrate the importance of the environment in keratoconus (KC) genesis. […] Genetic-related connective tissue disorders demonstrate the inconsistency of theories regarding KC pathogenesis since no corneal steepening was observed in the majority of these patients. […] Despite recent advances and decades of research into the genetics of KC, the identification of disease-causing KC genes has been frustrating. […] Variants found based on genome-wide and next-generation sequencing only seem to account for a small number of cases or play a limited role in KC pathogenesis. […] The literature shows that mechanical manipulation may be the common underlying factor or the indispensable act precipitating the cascade of events leading to permanent corneal deformation.

• #26 What is Keratoconus? – Defeat Keratoconus

  https://defeatkeratoconus.com/what-is-keratoconus/

  Keratoconus has long been regarded as a dystrophy of unknown origin. The morphological deformation inflicted on the corneal wall in keratoconus is pronounced, but the relative absence of specific genetic and biomolecular abnormalities makes this disease an ophthalmic enigma. […] A mechanical disease caused by repetitive and vigorous eye rubbing. […] The authors of this website have acquired the certitude that the root cause of keratoconus is eye rubbing. This assertion, which is difficult to prove, but equally difficult to refute, derives from crossed observations and follow-up of hundreds of keratoconus cases. […] Recent biomechanical investigations have shown that corneas with keratoconus are focally but not globally weakened. In keratoconus, the central portion of the cornea is thinned and weakened, whereas its periphery shows a normal biomechanical behavior.

• #27

  https://www.healio.com/news/optometry/20180309/surgeon-proposes-keratoconus-is-caused-by-eye-rubbing

  Damien Gatinel, PhD, MD, strongly believes that keratoconus is caused by patients rubbing their eyes and sleeping with their faces against the pillow. […] In my opinion, from assessing the logical evidence and clinical investigation, the root cause of KCN is undeniably eye rubbing. Without exertion of local and repeated corneal trauma leading to focal weakening of the corneal stroma, I do not believe that the classic picture of KCN can occur spontaneously. […] The repeated mechanical stress exerted against the corneal dome weakens the corneal tissue through pathways both mechanical and biological. […] Over time, repeated rubbing leads to a permanent corneal warpage via the combination of mechanical and biological factors. […] Eye rubbing does not only fuel KCN progression, but it may be the prime hit in the pathway toward KCN.

• #28 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Research strategies to unravel KC pathogenesis include histochemistry, biomechanics, enzymology, proteomics, and molecular genetics. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowman’s layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma.

• #29 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Importantly, although the development of disease involves complex interactions between genetic and environmental factors, their relative contributions to disease are currently unknown and likely to be variable. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowmans layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] Examination of the proteome of KC tissue has confirmed that, compared with normal cornea, there is upregulation of decorin and keratocan.

• #30 Keratoconus – EyeWiki

  https://eyewiki.org/Keratoconus

  Keratoconus is an uncommon corneal disorder where the central or paracentral cornea undergoes progressive thinning and steepening, causing irregular astigmatism. […] The etiology is unknown, but several factors leading to progression have been described. Inheritance and environmental factors are suggested to play a role in the pathogenesis of ectatic corneal diseases, with 8% resulting from genetic mutations and 92% from environmental factors. […] Keratoconus is associated with atopy and eye rubbing. Eye rubbing and repeated trauma in genetically predisposed individuals results in keratoconus and its progression. […] Histopathology studies demonstrated breaks in or complete absence of Bowman layer, collagen disorganization, scarring, and thinning. The etiology of these changes is unknown, though some suspect changes in enzymes that lead to the breakdown of collagen in the cornea.

• #31 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Pathological changes seen in KC relate to the underlying, usually bilateral but asymmetric, thinning and ectasia of the cornea. […] The most marked changes in KC are seen in the corneal stroma, especially in the region of the cone. […] The characteristic cone can be small and round, central nipple cone, or oval shaped, and predominantly inferonasal or an inferotemporal oval cone. […] Epithelial abnormalities such as blebbing, thinning, and degeneration are noted early in KC. […] Fragmentation of Bowmans layer is a common feature seen in 70% of cases, especially those with oval cones. […] The reduction of keratocyte density, attributed to accelerated keratocyte apoptosis, is also seen as a consistent feature on IVCM. […] Although KC is traditionally regarded as a non-inflammatory corneal disease, emerging evidence suggests that inflammation plays a key role in the etiopathogenesis of KC.

• #32 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] Stromal thinning, a hallmark of KC, is caused by a reduction in the number of lamellae within the affected region rather than compaction of collagen fibrils within individual lamellae, but the mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] The reported prevalence of KC is highly variable ranging from 2340 per 100000 in Israel to 0.20.4 per 100000 in Russia. […] Although the majority of cases of KC are sporadic, reports of familial cases of KC are also common and aggregation of the disease in families is often observed.

• #33 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Pathological changes seen in KC relate to the underlying, usually bilateral but asymmetric, thinning and ectasia of the cornea. […] The most marked changes in KC are seen in the corneal stroma, especially in the region of the cone. […] The characteristic cone can be small and round, central nipple cone, or oval shaped, and predominantly inferonasal or an inferotemporal oval cone. […] Epithelial abnormalities such as blebbing, thinning, and degeneration are noted early in KC. […] Fragmentation of Bowmans layer is a common feature seen in 70% of cases, especially those with oval cones. […] The reduction of keratocyte density, attributed to accelerated keratocyte apoptosis, is also seen as a consistent feature on IVCM. […] Although KC is traditionally regarded as a non-inflammatory corneal disease, emerging evidence suggests that inflammation plays a key role in the etiopathogenesis of KC.

• #34 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Pathological changes seen in KC relate to the underlying, usually bilateral but asymmetric, thinning and ectasia of the cornea. […] The most marked changes in KC are seen in the corneal stroma, especially in the region of the cone. […] The characteristic cone can be small and round, central nipple cone, or oval shaped, and predominantly inferonasal or an inferotemporal oval cone. […] Epithelial abnormalities such as blebbing, thinning, and degeneration are noted early in KC. […] Fragmentation of Bowmans layer is a common feature seen in 70% of cases, especially those with oval cones. […] The reduction of keratocyte density, attributed to accelerated keratocyte apoptosis, is also seen as a consistent feature on IVCM. […] Although KC is traditionally regarded as a non-inflammatory corneal disease, emerging evidence suggests that inflammation plays a key role in the etiopathogenesis of KC.

• #35 Atlas Entry – Vogt’s striae in keratoconus

  https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/vogts-striae.htm

  Vogt’s striae are vertical (rarely horizontal) fine, whitish lines in the deep/posterior stroma and Descemet’s membrane commonly found in patients with keratoconus. […] There is a positive correlation between the orientation of the lines with the steepest axis of the cornea and the mechanism is thought to be related to mechanical stress forces on collagen lamellae radiating from the cone apex. […] The striae can temporarily disappear with external pressure to the globe.

• #36 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] Stromal thinning, a hallmark of KC, is caused by a reduction in the number of lamellae within the affected region rather than compaction of collagen fibrils within individual lamellae, but the mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] The reported prevalence of KC is highly variable ranging from 2340 per 100000 in Israel to 0.20.4 per 100000 in Russia. […] Although the majority of cases of KC are sporadic, reports of familial cases of KC are also common and aggregation of the disease in families is often observed.

• #37 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma. […] The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] The mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] This theory is supported by the observation of reduced inter-lamellar adhesion, lamellar interlacing in the apex of KC corneas and a reduced number of lamellar insertions into Bowman’s layer.

• #38 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] Stromal thinning, a hallmark of KC, is caused by a reduction in the number of lamellae within the affected region rather than compaction of collagen fibrils within individual lamellae, but the mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] The reported prevalence of KC is highly variable ranging from 2340 per 100000 in Israel to 0.20.4 per 100000 in Russia. […] Although the majority of cases of KC are sporadic, reports of familial cases of KC are also common and aggregation of the disease in families is often observed.

• #39 Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis | Cell Discovery

  https://www.nature.com/articles/s41421-022-00397-z

  In corneal stromal cells, we identified two novel keratoconus-related markers, namely cathepsin D (CTSD) and cathepsin K (CTSK). […] We also detected the up-regulation of the mechano-transducer YES-associated protein 1 (YAP1) as well as its cooperator TEA domain transcription factor (TEAD1) in keratoconus stromal cells. […] Further cyclical mechanical experiments revealed that several protease genes (including MMP1, MMP3, CTSD and CTSK) can be induced by stretch, indicating the inductive role of mechanical stretch in keratoconus pathogenesis. […] These results orchestrated the pathogenic role of biomechanics-enzymes axis in keratoconus progress, providing explanations for the clinical phenomenon that mechanical stimuli can lead to the onset and exacerbation of keratoconus symptom. […] Overall, this study provided valuable resources for understanding keratoconus pathogenesis, offering further insights to improve preventative and therapeutic strategies for this disease.

• #40 Keratoconus – Wikipedia

  https://en.wikipedia.org/wiki/Keratoconus

  A number of studies have indicated keratoconic corneas show signs of increased activity by proteases, a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors. […] Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea. […] Whatever the pathogenetical process, the damage caused by activity within the cornea likely results in a reduction in its thickness and biomechanical strength. […] At an ultrastructural level the weakening of the corneal tissue is associated with a disruption of the regular arrangement of the collagen layers and collagen fibril orientation. […] While keratoconus is considered a noninflammatory disorder, one study shows wearing rigid contact lenses by people leads to overexpression of proinflammatory cytokines, such as IL-6, TNF-alpha, ICAM-1, and VCAM-1 in the tear fluid. […] Researches also have shed light on the role of hormones in the pathophysiology of keratoconus.

• #41

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Kenney et al. (2005) found that keratoconus corneas exhibited a 2.20-fold increase in catalase (115500) mRNA and 1.8-fold increase in enzyme activity; a 1.5-fold increase in cathepsis V/L2 (603308) mRNA and abnormal protein distribution; and a 1.8-fold decrease in TIMP1 (305370) mRNA and a 2.8-fold decrease in protein compared with normal (physiologic) corneas. Kenney et al. (2005) concluded that keratoconus corneas had elevated levels of cathepsins V/L2, B (116810), and G (116830), which could stimulate hydrogen peroxide production, which, in turn, could upregulate catalase, an antioxidant enzyme. In addition, decreased TIMP1 and increased cathepsin V/L2 levels might play a role in the matrix degradation that is a hallmark of keratoconus corneas. These findings supported the hypothesis that keratoconus corneas undergo oxidative stress and tissue degradation.

• #42 Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis | Cell Discovery

  https://www.nature.com/articles/s41421-022-00397-z

  In corneal stromal cells, we identified two novel keratoconus-related markers, namely cathepsin D (CTSD) and cathepsin K (CTSK). […] We also detected the up-regulation of the mechano-transducer YES-associated protein 1 (YAP1) as well as its cooperator TEA domain transcription factor (TEAD1) in keratoconus stromal cells. […] Further cyclical mechanical experiments revealed that several protease genes (including MMP1, MMP3, CTSD and CTSK) can be induced by stretch, indicating the inductive role of mechanical stretch in keratoconus pathogenesis. […] These results orchestrated the pathogenic role of biomechanics-enzymes axis in keratoconus progress, providing explanations for the clinical phenomenon that mechanical stimuli can lead to the onset and exacerbation of keratoconus symptom. […] Overall, this study provided valuable resources for understanding keratoconus pathogenesis, offering further insights to improve preventative and therapeutic strategies for this disease.

• #43

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Kenney et al. (2005) found that keratoconus corneas exhibited a 2.20-fold increase in catalase (115500) mRNA and 1.8-fold increase in enzyme activity; a 1.5-fold increase in cathepsis V/L2 (603308) mRNA and abnormal protein distribution; and a 1.8-fold decrease in TIMP1 (305370) mRNA and a 2.8-fold decrease in protein compared with normal (physiologic) corneas. Kenney et al. (2005) concluded that keratoconus corneas had elevated levels of cathepsins V/L2, B (116810), and G (116830), which could stimulate hydrogen peroxide production, which, in turn, could upregulate catalase, an antioxidant enzyme. In addition, decreased TIMP1 and increased cathepsin V/L2 levels might play a role in the matrix degradation that is a hallmark of keratoconus corneas. These findings supported the hypothesis that keratoconus corneas undergo oxidative stress and tissue degradation.

• #44 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Patients with KC were reported to have a higher level of free radicals and other reactive species in their corneas, than control samples. […] An elevated amount of endothelial nitric oxide synthase (eNOS) at the site of Bowman’s layer breaks was observed in KC indicating an increased production of nitric oxide in these corneal regions. […] Excessive RNS generation can contribute to modification of the stromal collagen molecules, increased apoptotic activity and KC corneal thinning. […] Decreased antioxidant defenses in KC corneas, and increased levels of ROS and RNS may lead to the degradation of the extracellular matrix in the stroma and modification of cellular compounds, making them more susceptible to degradation, and thus result in thinner stroma in KC. […] Keratoconus corneas presented an increased level of mitochondrial DNA (mtDNA) damage, compared with age-matched normal corneas.

• #45 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Patients with KC were reported to have a higher level of free radicals and other reactive species in their corneas, than control samples. […] An elevated amount of endothelial nitric oxide synthase (eNOS) at the site of Bowman’s layer breaks was observed in KC indicating an increased production of nitric oxide in these corneal regions. […] Excessive RNS generation can contribute to modification of the stromal collagen molecules, increased apoptotic activity and KC corneal thinning. […] Decreased antioxidant defenses in KC corneas, and increased levels of ROS and RNS may lead to the degradation of the extracellular matrix in the stroma and modification of cellular compounds, making them more susceptible to degradation, and thus result in thinner stroma in KC. […] Keratoconus corneas presented an increased level of mitochondrial DNA (mtDNA) damage, compared with age-matched normal corneas.

• #46 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Patients with KC were reported to have a higher level of free radicals and other reactive species in their corneas, than control samples. […] An elevated amount of endothelial nitric oxide synthase (eNOS) at the site of Bowman’s layer breaks was observed in KC indicating an increased production of nitric oxide in these corneal regions. […] Excessive RNS generation can contribute to modification of the stromal collagen molecules, increased apoptotic activity and KC corneal thinning. […] Decreased antioxidant defenses in KC corneas, and increased levels of ROS and RNS may lead to the degradation of the extracellular matrix in the stroma and modification of cellular compounds, making them more susceptible to degradation, and thus result in thinner stroma in KC. […] Keratoconus corneas presented an increased level of mitochondrial DNA (mtDNA) damage, compared with age-matched normal corneas.

• #47 Keratoconus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1194693-overview

  Abnormal oxidative stress-related properties have been found in keratoconic corneal cells. […] Oxidative stress elements can induce activation of degradative enzymes and degradation of tissue inhibitors of metal-low proteinases. […] Genomic deletion in the superoxide dismutase 1 (SOD1) gene also has been associated with the disease. […] Although usually believed to be noninflammatory, some data suggest an inflammatory component.

• #48 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Patients with KC were reported to have a higher level of free radicals and other reactive species in their corneas, than control samples. […] An elevated amount of endothelial nitric oxide synthase (eNOS) at the site of Bowman’s layer breaks was observed in KC indicating an increased production of nitric oxide in these corneal regions. […] Excessive RNS generation can contribute to modification of the stromal collagen molecules, increased apoptotic activity and KC corneal thinning. […] Decreased antioxidant defenses in KC corneas, and increased levels of ROS and RNS may lead to the degradation of the extracellular matrix in the stroma and modification of cellular compounds, making them more susceptible to degradation, and thus result in thinner stroma in KC. […] Keratoconus corneas presented an increased level of mitochondrial DNA (mtDNA) damage, compared with age-matched normal corneas.

• #49

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Lema and Duran (2005) determined the levels of a panel of inflammatory molecules and matrix metalloproteinases in the tears of patients with keratoconus. Patients with keratoconus had significantly higher levels of IL6 (147620), TNFA (191160), and MMP9 (120361) than control subjects. The extent of the increase was associated with the severity of keratoconus. Lema and Duran (2005) suggested that the pathogenesis of keratoconus may involve chronic inflammatory events. […] Atilano et al. (2005) found that keratoconus-affected corneas showed a trend of lower mtDNA-to-nDNA ratio than did control corneas, had decreased cytochrome c oxidase subunit I (MTCO1; 516030) in areas of corneal thinning, and had significantly increased numbers of mtDNA deletions compared to control corneas. Atilano et al. (2005) suggested that increased oxidative stress and altered integrity of mtDNA may be related to each other, contributing to keratoconus pathogenesis.

• #50 Keratoconus – EyeWiki

  https://eyewiki.org/Keratoconus

  While a genetic predisposition to keratoconus is suggested, a specific gene has not been identified. […] Studies show a significant role of proteolytic enzymes, cytokines, and free radicals (matrix metalloproteinase 9 [MMP-9], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-]) even in subclinical disease, showing a quasi-inflammatory characteristic in keratoconus. […] Tear film biomarkers, like IL-6, TNF-, and MMP-9, which were overexpressed in tears of keratoconus patients, indicating pathogenesis of keratoconus might involve chronic inflammatory events.

• #51

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Lema and Duran (2005) determined the levels of a panel of inflammatory molecules and matrix metalloproteinases in the tears of patients with keratoconus. Patients with keratoconus had significantly higher levels of IL6 (147620), TNFA (191160), and MMP9 (120361) than control subjects. The extent of the increase was associated with the severity of keratoconus. Lema and Duran (2005) suggested that the pathogenesis of keratoconus may involve chronic inflammatory events. […] Atilano et al. (2005) found that keratoconus-affected corneas showed a trend of lower mtDNA-to-nDNA ratio than did control corneas, had decreased cytochrome c oxidase subunit I (MTCO1; 516030) in areas of corneal thinning, and had significantly increased numbers of mtDNA deletions compared to control corneas. Atilano et al. (2005) suggested that increased oxidative stress and altered integrity of mtDNA may be related to each other, contributing to keratoconus pathogenesis.

• #52 Keratoconus: the possible involvement of inflammatory cytokines in its pathogenesis. An experimental study and review of the literature

  https://www.europeanreview.org/article/26239

  Keratoconus (KC) is generally described as a non-inflammatory disease, characterized by thinning in the central region of the cornea with consequent tissue degradation producing impaired visual acuity. […] The analysis showed increased levels of inflammatory factors in the pathological tissues compared to controls, confirming that KC cannot be considered an entirely non-inflammatory pathology and that its etiopathogenesis includes several chronic inflammatory events. […] In the light of these results, the classification of KC as an inflammatory pathology or as a pathology related to inflammation might be useful in directing future research aimed at developing effective anti-inflammatory therapies to pharmacologically target the inflammatory mediators which contribute to the development and progression of the disease.

• #53 The candidate proteins associated with keratoconus: A meta-analysis and bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299739

  Keratoconus (KC) is a multifactorial disorder. This study aimed to conduct a systematic meta-analysis to exclusively explore the candidate proteins associated with KC pathogenesis. […] KC is a multifactorial disorder including genetic and environmental factors. […] It has also been reported that oxidative damage in KC may be related to mitochondrial dysfunction. […] However, growing evidence reveals its association with ocular inflammation, particularly increased levels of inflammatory cytokines in the tear fluid of KC. […] Dynamic changes of inflammatory factors activate metalloproteinases, promote cell apoptosis, and contribute to corneal oxidative damage. […] A recent study found that the ligand-receptor interaction of anti-inflammatory processes is eliminated in cone cornea. […] Meanwhile, it also suggested that immune pathways might be involved in the pathogenesis of KC, which has been positively associated with a variety of immune-mediated diseases including allergic rash and asthma.

• #54 Modern Pathogenesis of Keratoconus: Genomics and Proteomics

  https://ouci.dntb.gov.ua/en/works/4LGAgpK7/

  Modern Pathogenesis of Keratoconus: Genomics and Proteomics […] The cascade hypothesis of keratoconus. […] Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. […] Keratocyte apoptosis associated with keratoconus. […] Increased gelatinolytic activity in keratoconus keratocyte cultures. A correlation to an altered matrix metalloproteinase-2/tissue inhibitor of metalloproteinase ratio. […] Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. […] Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. […] Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.

• #55

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Because matrix degrading enzymes could potentially influence keratoconus progression, Matthews et al. (2007) studied the effects of TIMP1 and TIMP3 (188826) on stromal cell viability. Overexpression of TIMP3 induced apoptosis in corneal stromal cell cultures. Upregulated TIMP1 production or the addition of exogenous TIMP1 protein prevented stromal cell overgrowth, changed stromal cell morphology, and reduced the extent of TIMP3 induced apoptosis. Localized relative concentrations of TIMP1/TIMP3 could thus determine whether cells remained viable or became apoptotic. Matthews et al. (2007) concluded that this might be relevant to keratoconus because significantly more apoptotic cells were identified in the anterior stroma of keratoconic corneas than in normal corneas and the majority of the TIMP1 and TIMP3 producing stromal cells were located in that region.

• #56 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma. […] The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] The mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] This theory is supported by the observation of reduced inter-lamellar adhesion, lamellar interlacing in the apex of KC corneas and a reduced number of lamellar insertions into Bowman’s layer.

• #57 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Research strategies to unravel KC pathogenesis include histochemistry, biomechanics, enzymology, proteomics, and molecular genetics. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowman’s layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma.

• #58 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Research strategies to unravel KC pathogenesis include histochemistry, biomechanics, enzymology, proteomics, and molecular genetics. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowman’s layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma.

• #59 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Importantly, although the development of disease involves complex interactions between genetic and environmental factors, their relative contributions to disease are currently unknown and likely to be variable. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowmans layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] Examination of the proteome of KC tissue has confirmed that, compared with normal cornea, there is upregulation of decorin and keratocan.

• #60 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Importantly, although the development of disease involves complex interactions between genetic and environmental factors, their relative contributions to disease are currently unknown and likely to be variable. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowmans layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] Examination of the proteome of KC tissue has confirmed that, compared with normal cornea, there is upregulation of decorin and keratocan.

• #61 Modern Pathogenesis of Keratoconus: Genomics and Proteomics

  https://ouci.dntb.gov.ua/en/works/4LGAgpK7/

  Modern Pathogenesis of Keratoconus: Genomics and Proteomics […] The cascade hypothesis of keratoconus. […] Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. […] Keratocyte apoptosis associated with keratoconus. […] Increased gelatinolytic activity in keratoconus keratocyte cultures. A correlation to an altered matrix metalloproteinase-2/tissue inhibitor of metalloproteinase ratio. […] Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. […] Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. […] Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.

• #62

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Shetty et al. (2015) studied the expression of select genes associated with corneal structure in a large cohort of patients with keratoconus (90 eyes) compared with patients undergoing photorefractive keratectomy who did not have keratoconus (52 eyes). Shetty et al. (2015) observed a significant reduction in lysyl oxidase (LOX; 153455) transcript levels in KTCN corneal epithelia, and LOX activity in KCTN tears correlated with disease severity. Collagen transcript levels (COL1A1, 120150; COL4A1, 120130) were also reduced in KCTN, whereas MMP9 (120361) transcript levels were upregulated and correlated with disease severity. IL6 (147620) transcript levels were moderately increased in KCTN patients. Immunohistochemistry demonstrated a reduction in the protein expression levels of LOX in the epithelium and COL4A1 in the basement membrane of KCTN patients (27 eyes) compared to healthy donor corneas (15 eyes). Shetty et al. (2015) concluded that the structural deformity of the KCTN cornea may be dependent on reduced expression of collagens and LOX, as well as on the concomitant increased expression of MMP9.

• #63 Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis | Cell Discovery

  https://www.nature.com/articles/s41421-022-00397-z

  In corneal stromal cells, we identified two novel keratoconus-related markers, namely cathepsin D (CTSD) and cathepsin K (CTSK). […] We also detected the up-regulation of the mechano-transducer YES-associated protein 1 (YAP1) as well as its cooperator TEA domain transcription factor (TEAD1) in keratoconus stromal cells. […] Further cyclical mechanical experiments revealed that several protease genes (including MMP1, MMP3, CTSD and CTSK) can be induced by stretch, indicating the inductive role of mechanical stretch in keratoconus pathogenesis. […] These results orchestrated the pathogenic role of biomechanics-enzymes axis in keratoconus progress, providing explanations for the clinical phenomenon that mechanical stimuli can lead to the onset and exacerbation of keratoconus symptom. […] Overall, this study provided valuable resources for understanding keratoconus pathogenesis, offering further insights to improve preventative and therapeutic strategies for this disease.

• #64 Single-cell atlas of keratoconus corneas revealed aberrant transcriptional signatures and implicated mechanical stretch as a trigger for keratoconus pathogenesis | Cell Discovery

  https://www.nature.com/articles/s41421-022-00397-z

  In corneal stromal cells, we identified two novel keratoconus-related markers, namely cathepsin D (CTSD) and cathepsin K (CTSK). […] We also detected the up-regulation of the mechano-transducer YES-associated protein 1 (YAP1) as well as its cooperator TEA domain transcription factor (TEAD1) in keratoconus stromal cells. […] Further cyclical mechanical experiments revealed that several protease genes (including MMP1, MMP3, CTSD and CTSK) can be induced by stretch, indicating the inductive role of mechanical stretch in keratoconus pathogenesis. […] These results orchestrated the pathogenic role of biomechanics-enzymes axis in keratoconus progress, providing explanations for the clinical phenomenon that mechanical stimuli can lead to the onset and exacerbation of keratoconus symptom. […] Overall, this study provided valuable resources for understanding keratoconus pathogenesis, offering further insights to improve preventative and therapeutic strategies for this disease.

• #65 The candidate proteins associated with keratoconus: A meta-analysis and bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299739

  Despite lots of studies gain insight into the understanding the fundamental pathogenesis of KC, its underlying mechanism remains unclear. […] Dysregulated gene expression has been reported in KC corneal tissue and stromal cells. […] RNA-Seq-based expression profiling using the whole cornea has identified the downregulation of core elements in TGF-, Hippo, and Wnt signaling pathways in KC pathogenesis. […] Integrative omics analyses of KC corneal epithelial tissues and blood samples uncovered a significant association between immune-inflammatory pathways and this disease. […] Our meta-analysis summarized the proteins that are disordered in multiple pathogenesis of KC, not limited to inflammatory response or oxidative stress. […] It will provide candidate proteins involved in KC pathogenesis and potential targets for KC treatment.

• #66 Pathophysiology of Keratoconus: What Do We Know Today

  https://www.openophthalmologyjournal.com/VOLUME/11/PAGE/252/FULLTEXT/

  This overall pro-oxidative environment was hypothesized to trigger the tissue destruction seen in KC. […] The ECM is produced by keratocytes. This process is regulated, amongst others, by TGF- signaling. […] Altogether, these findings suggest that the TGF- pathway may be an important effector route in KC and warrant further research. […] Overall, it appears that KC may be caused by an aberrant tissue response to one or more unidentified stimuli that subsequently leads to keratocyte depletion or dysfunction, loss of collagen, and ultimately a biomechanically weak cornea with a degenerated ECM.

• #67 Painting a Clearer Picture of Corneal Scarring in Keratoconus – Modern Optometry

  https://modernod.com/articles/2025-mar-apr/painting-a-clearer-picture-of-corneal-scarring-in-keratoconus

  The etiology and pathogenesis of keratoconus is complex and not fully understood. In simplest terms, it is considered a multifaceted amalgamation of factors including systemic conditions, genetic predispositions, and environmental factors such as contact lens wear, chronic eye rubbing, and allergies. […] Progressive or untreated keratoconus results in stromal collagen thinning, basement membrane (BM) disorganization, Bowman layer breaks, corneal fibrosis, and ultimately, vision loss. […] Previous studies have indicated the TGF- signaling pathway as a developing target for reducing and preventing corneal fibrosis seen in keratoconus. […] More recent animal studies and clinical trials further identified that topical losartan indirectly inhibits stromal TGF-, thereby reducing corneal fibrosis.

• #68 Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms

  https://www.mdpi.com/2218-273X/13/4/696

  Collagen crosslinking (CXL) is a widely used treatment to halt the progression of keratoconus (KC). […] The Wnt signaling pathway plays a major role in normal corneal development, with Wnt7b and Wnt10a reported to be associated with an increased risk of KC development. […] Wnt signaling has only recently been linked to KC, while corneal fibrosis and its markers are known factors in the pathobiology of this disease. […] The data shown in this study provide a better understanding of CXL. […] Our previous published work highlights the importance and novelty of our in vitro approaches, whereas the data reported herein indicates its potential. […] The long-term outcomes of CXL are still under investigation given the relatively short time since the modality was approved and widely adopted.

• #69 Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms

  https://www.mdpi.com/2218-273X/13/4/696

  Wnt signaling modulation has been reported in KCs, largely focused on the epithelium and through RNA-Seq approaches. […] Taken together, our study highlights the involvement of Wnt signaling with CXL and possibly indicates the existence of an intricate mechanism that needs to be further studied. […] The contributions of the ECM to the physiologic actions of prolactin are increasingly investigated; however, very little is known about the functional relationship between ECM and prolactin signaling in CXL. […] Insights into the molecular pathways of KC and CXL may ultimately expand treatment options for patients suffering from KC.

• #70 The candidate proteins associated with keratoconus: A meta-analysis and bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299739

  Despite lots of studies gain insight into the understanding the fundamental pathogenesis of KC, its underlying mechanism remains unclear. […] Dysregulated gene expression has been reported in KC corneal tissue and stromal cells. […] RNA-Seq-based expression profiling using the whole cornea has identified the downregulation of core elements in TGF-, Hippo, and Wnt signaling pathways in KC pathogenesis. […] Integrative omics analyses of KC corneal epithelial tissues and blood samples uncovered a significant association between immune-inflammatory pathways and this disease. […] Our meta-analysis summarized the proteins that are disordered in multiple pathogenesis of KC, not limited to inflammatory response or oxidative stress. […] It will provide candidate proteins involved in KC pathogenesis and potential targets for KC treatment.

• #71 Pathogenesis and genetic causes of keratoconus – Shukti Chakravarti Lab

  https://www.shukti-chakravarti-lab.org/extracellular-matrix-changes-and-underlying-genetic-causes-in-a-degenerative-corneal-disease-called-keratoconus/

  Keratoconus is a degenerative thinning and weakening of the corneal ECM, consequent bulging of the cornea with progressive loss of vision. […] While the etiology of keratoconus is not fully understood, interactions of genetic factors with environmental stressors are suspected. […] The pathogenic cellular and ECM changes in keratoconus are increasingly thought to be due to the accumulation of multiple deleterious genetic variants in an individual. […] Additionally, we are studying the transcriptomes and proteomes of corneas in keratoconus subjects undergoing corneal transplantation to identify significant regulatory signaling networks in keratoconus. […] We identified increased expression of stress response genes, while expression of ECM genes, NRF2-regulated antioxidant and tissue-injury response related genes were decreased in keratoconus. […] These studies will identify major genes, biomarkers and pathway that contribute to keratoconus that may be used to improve diagnoses and treatments for keratoconus.

• #72 What Causes Keratoconus| KC theories | Genetic/Environmental

  https://nkcf.org/about-keratoconus/what-causes-keratoconus/

  The exact cause of keratoconus is unknown. There are many theories based on research and its association with other conditions. However, no one theory explains it all and it may be caused by a combination of things. […] It is believed that genetics, the environment and the endocrine system all play a role in keratoconus. […] One scientific view is that keratoconus is developmental (i.e., genetic) in origin because in some cases there does appear to be a familial association. […] Some studies show that keratoconus corneas lack important anchoring fibrils that structurally stabilize the anterior cornea. This increased flexibility allows that cornea to “bulge forward” into a cone-shaped appearance. […] Some studies indicate an abnormal processing of the superoxide radicals in the keratoconus cornea and an involvement of oxidative stress in the pathogenesis of this disease. Keratoconus corneas lack the ability to self-repair routine damage easily repaired by normal corneas. […] Another hypothesis is that the endocrine system may be involved because keratoconus is generally first detected at puberty and progresses during pregnancy. This theory is still controversial and has not been proven.

• #73

  https://journals.lww.com/ijo/fulltext/2013/61080/genetic_and_genomic_perspective_to_understand_the.5.aspx

  The potential candidate genes in KC were selected based on the previously published association with other corneal disorders (corneal dystrophies) and their known functions in the eye development. […] The association of HGF with KC suggests the potential involvement of inflammatory pathway, moreover it has been shown as a risk factor for refractive error in several populations including Han Chinese and Caucasians. […] So far genetic studies have suggested that KC has clinical variability and may be linked to multiple chromosomal regions, consistent with polygenic mode of inheritance. […] In conclusion, both genetic and proteomic approaches together should provide further information on disease pathogenesis which can lead to better management of the disease.

• #74 New Evidence Strengthens the Link Between Air Pollution and Keratoconus

  https://www.reviewofoptometry.com/article/new-evidence-strengthens-the-link-between-air-pollution-and-keratoconus

  A recent study published in Ophthalmic Epidemiology highlights the connection between air pollution and keratoconus, revealing that fine particulate matter (PM2.5 and PM10) and nitrogen dioxide (NO2) may aggravate the condition. Researchers found that pollution could affect corneal structure directly and stimulate known risk factors such as eye rubbing and atopy. […] The three most implicated factors in the pathogenesis of keratoconus are UV radiation, eye rubbing and atopy. […] This research suggests pollution can affect the cornea both directly and indirectly, they said. The indirect pathway involves the stimulation of recognized risk factors for keratoconus, such as eye rubbing and atopy, they wrote. […] Patients with keratoconus may be more sensitive to the accumulation of reactive oxygen species, associated with air pollution, in the cornea, which could elevate the rate of cell death and contribute to corneal thinning, according to the study authors. This process may induce the development of keratoconus in genetically predisposed individuals and exacerbate its evolution where its already present, they wrote. […] Although further research is needed, this study appears to show that air pollution influences keratoconus development indirectly by stimulating eye rubbing and atopy, and that fine particles may directly affect corneal structures and increase cell apoptosis, the authors concluded.

• #75 Beyond The Cornea: The Complex Interplay of Genetics and Environment in Keratoconus – Vision Science Academy

  https://visionscienceacademy.org/beyond-the-cornea-the-complex-interplay-of-genetics-and-environment-in-keratoconus/

  Keratoconus pathogenesis is influenced by both hereditary and environmental factors. […] Keratoconus is caused by a complex mix of environmental and genetic factors. Eye rubbing, atopy, and UV exposure are all environmental variables. Excessive levels of any of the components induce oxidative damage to keratoconus corneas due to the inability of keratoconus to handle reactive oxygen species, resulting in a degradation process that results in corneal thinning and vision loss. […] Keratoconus pathogenesis is heavily influenced by genetics. Some of the origins of genetics include familial inheritance, discordance between dizygotic twins, and other recognized genetic abnormalities. […] In keratoconus-affected corneas, a buildup of cytotoxic byproducts breaks mitochondrial DNA and causes high levels of oxidative stress. The involvement of VSX1 (visual system homeobox 1) and SOD1 (superoxide dismutase 1) in the development of keratoconus is influenced by genetic variables. The most prevalent family keratoconus pattern is autosomal dominant and sporadic. […] Both environmental and genetic factors contribute to the pathogenesis of keratoconus, with eye rubbing being the most important risk factor, followed by allergies and sun exposure.

• #76 More to keratoconus than meets the cornea: Be sure to flip the lids

  https://www.ophthalmologytimes.com/view/more-to-keratoconus-than-meets-the-cornea-be-sure-to-flip-the-lids

  Keratoconus is characterized by noninflammatory progressive thinning of the cornea. […] While the precise etiology of keratoconus is unclear, it is suspected to occur from a combination of genetic, environmental, and hormonal influences. […] The authors determined that the most significant risk factor for keratoconus was eye rubbing, reporting that study participants with eye rubbing, regardless of their degree of atopy, were at a 5-7 times higher risk of developing keratoconus. […] Thus, the most likely mechanism by which atopy might contribute to keratoconus is through the eye rubbing tendency of atopic patients. […] The act of eye rubbing then releases inflammatory cytokines, which have been associated with the progression of keratoconus. […] In keratoconus, one study proposed the mechanism that damaged epithelial cells could activate MMP-2 via induced (Membrane type 1) MT1-MMP, causing degradation of the basement membrane; this would lead to cytokine diffusion from the damaged epithelium to the stroma and promote (Interleukin-1) IL-1-mediated inflammation.

• #77 The candidate proteins associated with keratoconus: A meta-analysis and bioinformatic analysis | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299739

  Keratoconus (KC) is a multifactorial disorder. This study aimed to conduct a systematic meta-analysis to exclusively explore the candidate proteins associated with KC pathogenesis. […] KC is a multifactorial disorder including genetic and environmental factors. […] It has also been reported that oxidative damage in KC may be related to mitochondrial dysfunction. […] However, growing evidence reveals its association with ocular inflammation, particularly increased levels of inflammatory cytokines in the tear fluid of KC. […] Dynamic changes of inflammatory factors activate metalloproteinases, promote cell apoptosis, and contribute to corneal oxidative damage. […] A recent study found that the ligand-receptor interaction of anti-inflammatory processes is eliminated in cone cornea. […] Meanwhile, it also suggested that immune pathways might be involved in the pathogenesis of KC, which has been positively associated with a variety of immune-mediated diseases including allergic rash and asthma.

• #78

  https://www.omim.org/entry/148300?search=keratoconus&highlight=keratoconus

  Shetty et al. (2015) studied the expression of select genes associated with corneal structure in a large cohort of patients with keratoconus (90 eyes) compared with patients undergoing photorefractive keratectomy who did not have keratoconus (52 eyes). Shetty et al. (2015) observed a significant reduction in lysyl oxidase (LOX; 153455) transcript levels in KTCN corneal epithelia, and LOX activity in KCTN tears correlated with disease severity. Collagen transcript levels (COL1A1, 120150; COL4A1, 120130) were also reduced in KCTN, whereas MMP9 (120361) transcript levels were upregulated and correlated with disease severity. IL6 (147620) transcript levels were moderately increased in KCTN patients. Immunohistochemistry demonstrated a reduction in the protein expression levels of LOX in the epithelium and COL4A1 in the basement membrane of KCTN patients (27 eyes) compared to healthy donor corneas (15 eyes). Shetty et al. (2015) concluded that the structural deformity of the KCTN cornea may be dependent on reduced expression of collagens and LOX, as well as on the concomitant increased expression of MMP9.

• #79 Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

  https://www.mdpi.com/1422-0067/14/9/19294

  Patients with KC were reported to have a higher level of free radicals and other reactive species in their corneas, than control samples. […] An elevated amount of endothelial nitric oxide synthase (eNOS) at the site of Bowman’s layer breaks was observed in KC indicating an increased production of nitric oxide in these corneal regions. […] Excessive RNS generation can contribute to modification of the stromal collagen molecules, increased apoptotic activity and KC corneal thinning. […] Decreased antioxidant defenses in KC corneas, and increased levels of ROS and RNS may lead to the degradation of the extracellular matrix in the stroma and modification of cellular compounds, making them more susceptible to degradation, and thus result in thinner stroma in KC. […] Keratoconus corneas presented an increased level of mitochondrial DNA (mtDNA) damage, compared with age-matched normal corneas.

• #80

  https://abp.ptbioch.edu.pl/index.php/abp/article/view/1923

  Keratoconus (KC) is a corneal disease associated with structural abnormalities in the corneal epithelium, Bowman’s layer and stroma and altered concentration of tear components. […] Altered expression and/or activity of lysyl oxidase, a critical enzyme of the biogenesis of connective tissue detected in KC corneas, may weaken covalent bonds between collagen and elastin fibrils, what may lead to biomechanical deterioration of the cornea. Increased activity of matrix metalloproteinases observed in KC may induce the degradation of the extracellular matrix causing damage to the cornea. […] Oxidative and nitrative stress play an important role in KC pathogenesis and KC corneas are characterized by the disturbed lipid peroxidation and nitric oxide pathways. Malfunctioning of these pathways may lead to accumulation of their toxic by-products inducing several detrimental effects, along with apoptosis of the corneal cells, which may result from the loss of -actin or increased levels of cytokines, including interleukin-1 and -6. Change in the expression of genes associated with wound healing, including the nerve growth factor and the visual system homeobox 1, may contribute to increased susceptibility of KC corneas to injury. Consequently, biochemical changes may play an important role in KC pathophysiology and, therefore, can be considered in prevention, diagnosis, prognosis and in the therapy of this disease as well.

• #81 Biomechanics of keratoconus: Two numerical studies | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278455

  The steep cornea in keratoconus can greatly impair eyesight. The etiology of keratoconus remains unclear but early injury that weakens the corneal stromal architecture has been implicated. […] These observations suggest that keratoconus could be initiated, at least partly, by mechanical instability/damage in the mid-posterior stroma that then imposes stress on the anterior layers. This may explain why subclinical keratoconus is marked by posterior but not anterior elevation on videokeratoscopy. […] Mechanical theory on laminated composites suggests that keratoconus is due to repeated excessive stress that results in progressive biomechanical failure of the cornea. Specifically, stress on the cornea could provoke two of the predominant mechanisms by which fiber-reinforced composites fail, namely, fiber breakage and interfiber cross-link breakage.

• #82 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma. […] The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] The mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] This theory is supported by the observation of reduced inter-lamellar adhesion, lamellar interlacing in the apex of KC corneas and a reduced number of lamellar insertions into Bowman’s layer.

• #83 Biomechanics of keratoconus: Two numerical studies | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278455

  We propose that in keratoconus, this phenomenon may be induced by the loss of interlamellar cross-links and the consequent slipping of lamellae over each other and away from the keratoconic button. […] Thus, we hypothesize that mechanical instability in a small area of the mid-posterior stroma due to loss of cross-links between the collagen lamellae may play an important early role in keratoconus pathogenesis.

• #84 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma. […] The corneal tissue in KC is less rigid than normal tissue and an increased axial length suggests a relationship with myopia. […] The mechanism by which the thinning occurs is uncertain. […] Although stromal thinning in KC has been attributed to collagen degradation by proteolytic enzymes or decreased levels of proteinase inhibitors, it has also been proposed that collagen is not lost but simply redistributed within the cornea by slippage between the lamellae. […] This theory is supported by the observation of reduced inter-lamellar adhesion, lamellar interlacing in the apex of KC corneas and a reduced number of lamellar insertions into Bowman’s layer.

• #85 Cornea St Petersburg | Keratoconus Tampa | Eye Institute

  https://www.eyespecialist.com/cornea-st-petersburg/keratoconus/

  Keratoconus results in a change of the corneal shape (the cornea assumes a conic shape), which does not allow for proper focusing of light onto the retina, resulting in decreased vision. […] The exact pathophysiological mechanism of keratoconus is unclear. We now understand that corneal collagen in patients with keratoconus is more elastic (softer, more expandable) allowing for ballooning of the cornea, resulting in deformation of the cornea. […] In simplistic terms, the skin (skin is mainly made from collagen) of babies is soft and elastic the same way the corneal collagen in younger patients is more elastic allowing for the aggressive progression of keratoconus. With age collagen shrinks and becomes stiffer (that is why as we age, we acquire wrinkles) and thereby the cornea in older patients is stiffer and retains its shape not allowing ballooning and deformation. […] The only available treatment that halts the progression of keratoconus with a success rate of 90% is corneal cross linking. After the introduction of corneal cross linking the need for corneal transplants in Europe for patients with keratoconus has decreased by more than 50%.

• #86 Keratoconus – EyeWiki

  https://eyewiki.org/Keratoconus

  Keratoconus is an uncommon corneal disorder where the central or paracentral cornea undergoes progressive thinning and steepening, causing irregular astigmatism. […] The etiology is unknown, but several factors leading to progression have been described. Inheritance and environmental factors are suggested to play a role in the pathogenesis of ectatic corneal diseases, with 8% resulting from genetic mutations and 92% from environmental factors. […] Keratoconus is associated with atopy and eye rubbing. Eye rubbing and repeated trauma in genetically predisposed individuals results in keratoconus and its progression. […] Histopathology studies demonstrated breaks in or complete absence of Bowman layer, collagen disorganization, scarring, and thinning. The etiology of these changes is unknown, though some suspect changes in enzymes that lead to the breakdown of collagen in the cornea.

• #87 Keratoconus: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1194693-overview

  Keratoconus is a progressive, assymetrically bilateral etatic corneal disease, characterized by paraxial corneal stromal thinning and steepening. […] Keratoconus is a progressive, assymetrically bilateral etatic corneal disease that causes decreased visual acuities, occurs primarily from irregular astigmatism and myopia induced from the corneal distortion, and secondarily from corneal scarring. […] All layers of the cornea are believed to be affected by keratoconus. Characteristic structural changes include epithelial basement membrane fragmentation and scarring, breaks in the anterior limiting lamina (ie, Bowman membrane), and axial stromal thinning and scarring. […] The literature on keratoconus is large and contradictory regarding the roles of disruption of collagen fibers, lamellae, and proteoglycans. Keratoconic corneas have been shown to have altered antioxidant enzymes, accumulations of cytotoxic reactive oxygen/nitrogen species, activated caspase pathways, and mitochondrial DNA damage.

• #88 Pathophysiology of Keratoconus | Ento Key

  https://entokey.com/pathophysiology-of-keratoconus/

  Pathological changes seen in KC relate to the underlying, usually bilateral but asymmetric, thinning and ectasia of the cornea. […] The most marked changes in KC are seen in the corneal stroma, especially in the region of the cone. […] The characteristic cone can be small and round, central nipple cone, or oval shaped, and predominantly inferonasal or an inferotemporal oval cone. […] Epithelial abnormalities such as blebbing, thinning, and degeneration are noted early in KC. […] Fragmentation of Bowmans layer is a common feature seen in 70% of cases, especially those with oval cones. […] The reduction of keratocyte density, attributed to accelerated keratocyte apoptosis, is also seen as a consistent feature on IVCM. […] Although KC is traditionally regarded as a non-inflammatory corneal disease, emerging evidence suggests that inflammation plays a key role in the etiopathogenesis of KC.

• #89 Connection between Keratoconus and DED | OBN

  https://ophthalmologybreakingnews.com/correlation-between-keratoconus-and-dry-eye-disease

  Keratoconus (KC) is a disorder of the eye that results in progressive thinning of the cornea. […] While the cause is unknown, it is believed to occur due to a combination of genetic, environmental, and hormonal factors. […] Proposed environmental factors include rubbing the eyes and allergies. The underlying mechanism involves changes of the cornea to a cone shape. […] Keratoconus is described as a bilateral but asymmetric, noninflammatory, progressive degeneration of the cornea, leading to extreme refractive errors with impaired visual acuity and conical corneal protrusion. […] Despite the historical description of keratoconus as a noninflammatory disease, inflammation may play a role in the progression of keratoconus. These data suggest that an inflammatory cycle much like that of dry eye may play an important role in keratoconus pathogenesis. […] While causality may be uncertain, managing eye rubbing, reducing inflammation, and reducing corneal microtrauma may improve the quality of life for patients with keratoconus.

• #90 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Research strategies to unravel KC pathogenesis include histochemistry, biomechanics, enzymology, proteomics, and molecular genetics. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowman’s layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] The majority of studies agree that in KC the stromal collagen content is decreased but that there are no dramatic changes in either the distribution of the various collagen types or in the cross-linking pattern and molecular arrangement of the collagen within the stroma.

• #91 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Importantly, although the development of disease involves complex interactions between genetic and environmental factors, their relative contributions to disease are currently unknown and likely to be variable. […] One of the first theories for the pathogenesis of KC was that the primary insult was an epithelial abnormality, resulting in the release of proteolytic enzymes that degrade stromal collagen to thin and weaken the cornea. […] However, with light microscopy there is additional evidence of major structural changes in other corneal layers, including breaks in Bowmans layer and stromal thinning. […] There is conflicting evidence regarding biochemical abnormalities in KC, with reports of increased, decreased, or normal levels of proteoglycans. […] Examination of the proteome of KC tissue has confirmed that, compared with normal cornea, there is upregulation of decorin and keratocan.

• #92 What Causes Keratoconus| KC theories | Genetic/Environmental

  https://nkcf.org/about-keratoconus/what-causes-keratoconus/

  The exact cause of keratoconus is unknown. There are many theories based on research and its association with other conditions. However, no one theory explains it all and it may be caused by a combination of things. […] It is believed that genetics, the environment and the endocrine system all play a role in keratoconus. […] One scientific view is that keratoconus is developmental (i.e., genetic) in origin because in some cases there does appear to be a familial association. […] Some studies show that keratoconus corneas lack important anchoring fibrils that structurally stabilize the anterior cornea. This increased flexibility allows that cornea to “bulge forward” into a cone-shaped appearance. […] Some studies indicate an abnormal processing of the superoxide radicals in the keratoconus cornea and an involvement of oxidative stress in the pathogenesis of this disease. Keratoconus corneas lack the ability to self-repair routine damage easily repaired by normal corneas. […] Another hypothesis is that the endocrine system may be involved because keratoconus is generally first detected at puberty and progresses during pregnancy. This theory is still controversial and has not been proven.

• #93 Causes – Keratoconus Specialists | Complete Family Eyecare

  https://www.keratoconusmn.com/causes/

  The exact cause of keratoconus remains elusive. Contributing factors seem to include genetic and possible hormonal factors but environmental factors may also play a role in the development of keratoconus. […] Keratoconus is much more common in males than females suggesting a possible hormonal component but an exact mechanism has never been determined. […] From an environmental perspective, there is some degree of correlation but no definitive numbers on the increase risk of keratoconus due to eye rubbing (feels really good but should be discouraged!). Excessive rubbing the eyes may put mechanical pressure on the cornea, further weakening the corneal structure. […] On a cellular level, keratoconus appears to be caused by the loss of Bowman’s layer of the corneal. The cornea is essentially transparent skin tissue and similar to other skin, the cornea is composed of different and distinct layers. Bowman’s layer lies beneath the outermost layer (epithelium) of the cornea and the middle layer of the cornea which is called the stroma. The stroma is the thickest layer of the cornea and is responsible for the majority of its strength and stability. Without the presence of Bowman’s layer, the stromal layer comes in direct contact with the epithelium and this interaction appears to cause the weakening of the stromal collagen and destabilization of the corneal. How this interaction occurs chemically is still another mystery with several theories involving enzymes, free radicals, and chemical inhibitors with gigantically long chemical names which we won’t go into. […] Although the true cause of keratoconus remains a mystery, ongoing research and new studies will hopefully shed some light on the root of this inconvenient condition.

• #94 Biomechanics of keratoconus: Two numerical studies | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278455

  We propose that in keratoconus, this phenomenon may be induced by the loss of interlamellar cross-links and the consequent slipping of lamellae over each other and away from the keratoconic button. […] Thus, we hypothesize that mechanical instability in a small area of the mid-posterior stroma due to loss of cross-links between the collagen lamellae may play an important early role in keratoconus pathogenesis.

• #95 Etiology of Keratoconus: proposed biomechanical pathogenesis | In Silico Cell and Tissue Science | Full Text

  https://in-silico-cell-and-tissue-science.springeropen.com/articles/10.1186/2196-050X-1-3

  The etiology of keratoconus most likely involves substantial biomechanical interactions. The goal of this study was to characterize corneal biomechanics using computer modeling techniques in order to elucidate the pathogenesis of keratoconus in biomechanical terms. […] We hypothesize that the etiology of keratoconus could be based solely on substantial biomechanical interactions. It has been previously purposed that pathological changes of the tissue structure might alter the mechanical properties of the cornea, which in turn can affect the gross shape of the cornea under IOP. […] Degradation of the circumferential fibers may very well be an initiating factor of a biomechanical process in which a bulge is gradually created from a presumably healthy cornea under normal underlying pressures and therefore, the identification of the early stages of keratoconus might be achievable by monitoring the in-vivo corneal fiber distribution.

• #96 OP-6 The involvement of corneal nerves in the pathogenesis of keratoconus | BMJ Open Ophthalmology

  https://bmjophth.bmj.com/content/9/Suppl_2/A2.3

  Seventy-one percent of keratoconic corneas demonstrated central stromal nerve changes, which included thickening, tortuosity, nerve spouting, and overgrowth. […] This study provides additional histologic evidence of the involvement of corneal nerves in keratoconus and suggests further that they may play a role in the pathogenesis and progression of the disease.

• #97 Blood Riboflavin Levels Significantly Lower in Keratoconus

  https://www.reviewofoptometry.com/news/article/blood-riboflavin-levels-significantly-lower-in-keratoconus

  This study found that riboflavin deficiency may play a role in the pathogenesis of keratoconus. […] Research has yet to confirm the pathogenesis of keratoconus, a disease characterized by progressive thinning and corneal steepening. […] Among their findings, published this month in the Journal of Cataract and Refractive Surgery, was that low blood riboflavin levels in keratoconus patients are a possible risk factor in the pathogenesis of the disease. […] The significant decrease in riboflavin levels detected in keratoconus subjects in our study indicates that riboflavin deficiency may have a potential role in the development of keratoconus, the researchers explained in their paper. […] In light of these results, the study authors stress that future studies should investigate the causes of low-endogenously synthesized riboflavin in keratoconus patients. A longitudinal study should also be conducted to determine whether progressive keratoconus is caused by an ongoing/worsening riboflavin deficiency, they concluded in their paper.

• #98 Keratoconus: Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/14415-keratoconus

  The cause of keratoconus is largely unknown. Some studies have found that keratoconus runs in families, and that it happens more often in people who have certain medical conditions. […] In most cases, you dont have an eye injury or a disease that leads to keratoconus. People with keratoconus tend to rub their eyes a lot, which may cause the condition to develop more rapidly. […] Corneal crosslinking uses ultraviolet (UV) light treatment that may slow or stop the keratoconus from getting worse. In this procedure, you also receive local anesthesia. Your provider puts drops of a drug containing riboflavin (vitamin B2) into your eye for up to 30 minutes. Then, your provider exposes your eye to an UV light for up to 30 minutes. The purpose of corneal crosslinking procedure is to strengthen the bonds between your corneas collagen fibers and surrounding proteins. This can help keep your corneas shape from getting steeper.

• #99 Corneal Cross-Linking – EyeWiki

  https://eyewiki.org/Corneal_Cross-Linking

  Corneal collagen crosslinking (CXL) is a minimally invasive procedure used to prevent progression of corneal ectasia such as keratoconus and post-LASIK ectasia. […] It has been hypothesized that this natural cross-linkage of collagen explains why keratectasia (corneal ectasia) often progresses most rapidly in adolescence or early adulthood but tends to stabilize in patients after middle-age. […] In the pathway most relevant to this topic, oxidation has been shown to be able to trigger corneal crosslinkage through the release of oxygen free radicals. […] The investigation also proved that treated corneas contained higher molecular weight polymers of collagen due to fibril crosslinking. […] The initial pilot study enrolled 16 patients with rapidly progressing keratoconus and all of the patients stopped progressing after treatment.

• #100 Corneal Cross-Linking – EyeWiki

  https://eyewiki.org/Corneal_Cross-Linking

  Corneal collagen crosslinking (CXL) is a minimally invasive procedure used to prevent progression of corneal ectasia such as keratoconus and post-LASIK ectasia. […] It has been hypothesized that this natural cross-linkage of collagen explains why keratectasia (corneal ectasia) often progresses most rapidly in adolescence or early adulthood but tends to stabilize in patients after middle-age. […] In the pathway most relevant to this topic, oxidation has been shown to be able to trigger corneal crosslinkage through the release of oxygen free radicals. […] The investigation also proved that treated corneas contained higher molecular weight polymers of collagen due to fibril crosslinking. […] The initial pilot study enrolled 16 patients with rapidly progressing keratoconus and all of the patients stopped progressing after treatment.

• #101 Corneal Cross-Linking – EyeWiki

  https://eyewiki.org/Corneal_Cross-Linking

  The primary purpose of cross-linking is to halt the progression of ectasia. […] The most common indication is keratoconus. […] CXL causes apoptosis of keratocytes in the anterior stroma, and in the following weeks, new keratocytes are found migrating from the periphery to the center. […] Hence, CXL alters normal corneal structure and cellularity at least for 36 months. […] Given the natural history of the disease, it is prudent to perform CXL when progression is documented. […] The authors of this study declared in their three year report the following pertinent statements: „The findings of this study suggest that CXL should continue to be considered as a treatment option for patients with progressive keratoconus.” […] „Despite the growing body of literature and continuing efforts to optimize the treatment protocol, there remains a lack of randomized controlled studies with longer-term follow-up to support the widespread clinical use of CXL for keratoconus.”

• #102 Painting a Clearer Picture of Corneal Scarring in Keratoconus – Modern Optometry

  https://modernod.com/articles/2025-mar-apr/painting-a-clearer-picture-of-corneal-scarring-in-keratoconus

  The etiology and pathogenesis of keratoconus is complex and not fully understood. In simplest terms, it is considered a multifaceted amalgamation of factors including systemic conditions, genetic predispositions, and environmental factors such as contact lens wear, chronic eye rubbing, and allergies. […] Progressive or untreated keratoconus results in stromal collagen thinning, basement membrane (BM) disorganization, Bowman layer breaks, corneal fibrosis, and ultimately, vision loss. […] Previous studies have indicated the TGF- signaling pathway as a developing target for reducing and preventing corneal fibrosis seen in keratoconus. […] More recent animal studies and clinical trials further identified that topical losartan indirectly inhibits stromal TGF-, thereby reducing corneal fibrosis.

• #103 Painting a Clearer Picture of Corneal Scarring in Keratoconus – Modern Optometry

  https://modernod.com/articles/2025-mar-apr/painting-a-clearer-picture-of-corneal-scarring-in-keratoconus

  By inhibiting TGF- signal transduction, losartan attenuates myofibroblast stimulation, triggering apoptosis or reversion back to keratocytes and eventual clearing of the corneal fibrosis. […] This mechanism has sparked interest in losartan as an off-label therapeutic indicated in the case of any fibrotic process caused by myofibroblasts, including keratoconus, post-surgical haze, thermal or chemical burns, microbial keratitis, herpes-related scarring, and other corneal dystrophies. […] By targeting the underlying TGF- signal transduction responsible for scarring, losartan can function as an adjunct to the mechanical stabilization achieved by CXL. […] Combining CXL and losartan in dual therapy could prevent continued corneal thinning while also reducing overall fibrosis. […] Early reports on topical ophthalmic losartan are exciting; however, they use limited ocular conditions, small sample sizes, short treatment intervals, and short follow-up periods. […] Looking to the future, the off-label role of topical losartan in optometry offers a promising novel alternative for those experiencing corneal scarring related to keratoconus or other fibrotic conditions.

• #104 Keratoconus | Theialife

  https://www.theialife.com/keratoconus

  Mechanism of action: rHCT3-2 eye drops improve corneal strength by promoting collagen crosslinking and inhibiting metalloproteinases enzymes responsible for collagen breakdown. This process enhances the bonding between collagen fibres, directly addressing the corneal thinning associated with keratoconus. […] By stabilizing and flattening the cornea, rHCT3-2 effectively counters the progressive weakening of the cornea. […] rHCT3-2 Eye drop functions by enhancing collagen crosslinking, a process that strengthens the cornea by increasing the bonds between collagen fibers. […] Specifically, it achieves this by inhibiting metalloproteinases, enzymes responsible for breaking down collagen molecules. […] By neutralizing these metalloproteinases, the eye drop promotes the stabilization and flattening of the cornea, which is crucial in managing conditions such as keratoconus. […] This mechanism helps improve corneal stability and visual outcomes in affected individuals.

• #105 Keratoconus and CPT-II deficiency – INFORM Network

  https://informnetwork.org/question/keratoconus-and-cpt-ii-deficiency/

  Keratoconus can be linked with cpt 2 deficiency. […] There is no demonstrated increase in the incidence in keratoconus in FAODs. […] The bottom line is that there is very little known about the presence and/or mechanism of its development. […] My own research suggests that there is and that it is related to secondary dysfunction of oxidative phosphorylation. […] However, this hypothesis needs more research to be proven. […] We are investigating a new family of mitochondrial targeted antioxidants and have published data showing that they are effective in reducing ROS in VLCAD deficient patient derived fibroblasts. […] In the meantime I don’t recommend using antioxidants as there is little or evidence showing benefit or identifying risks.

• #106 Keratoconus stabilization – Defeat Keratoconus

  https://defeatkeratoconus.com/keratoconus-stabilization/

  Keratoconus progression can be halted by suppressing the root mechanism of the corneal deformation at play: EYE RUBBING […] keratoconus progression per se has not been consistently or clearly defined. […] Progression (or stabilization) of the corneal deformation must be assessed by reliable examinations. […] The difference map provides an objective metric to monitor the evolution of the corneal deformation, which is the hallmark of keratoconus. […] If one considers that the primary cause of keratoconus is eye rubbing, it is logical that the cessation of rubbing suffices in stabilizing the disease. […] All patients who have been diagnosed with keratoconus and monitored for progression after they had ceased to rub their eyes are reported in this website. Differential maps were performed systematically at each examination to confirm the absence of keratoconus progression.

• #107

  https://www.healio.com/news/optometry/20180309/surgeon-proposes-keratoconus-is-caused-by-eye-rubbing

  If our assumption that eye rubbing is responsible for the onset and evolution of the disease is correct, then the cessation of eye rubbing must, at least in the early and moderate forms, stop the progression of KCN. […] I strongly believe that the origin of KCN may be elucidated and that eye rubbing is the all-important causative factor for this disease.

• #108 More to keratoconus than meets the cornea: Be sure to flip the lids

  https://www.ophthalmologytimes.com/view/more-to-keratoconus-than-meets-the-cornea-be-sure-to-flip-the-lids

  Keratoconus is characterized by noninflammatory progressive thinning of the cornea. […] While the precise etiology of keratoconus is unclear, it is suspected to occur from a combination of genetic, environmental, and hormonal influences. […] The authors determined that the most significant risk factor for keratoconus was eye rubbing, reporting that study participants with eye rubbing, regardless of their degree of atopy, were at a 5-7 times higher risk of developing keratoconus. […] Thus, the most likely mechanism by which atopy might contribute to keratoconus is through the eye rubbing tendency of atopic patients. […] The act of eye rubbing then releases inflammatory cytokines, which have been associated with the progression of keratoconus. […] In keratoconus, one study proposed the mechanism that damaged epithelial cells could activate MMP-2 via induced (Membrane type 1) MT1-MMP, causing degradation of the basement membrane; this would lead to cytokine diffusion from the damaged epithelium to the stroma and promote (Interleukin-1) IL-1-mediated inflammation.

• #109 Beyond The Cornea: The Complex Interplay of Genetics and Environment in Keratoconus – Vision Science Academy

  https://visionscienceacademy.org/beyond-the-cornea-the-complex-interplay-of-genetics-and-environment-in-keratoconus/

  Keratoconus pathogenesis is influenced by both hereditary and environmental factors. […] Keratoconus is caused by a complex mix of environmental and genetic factors. Eye rubbing, atopy, and UV exposure are all environmental variables. Excessive levels of any of the components induce oxidative damage to keratoconus corneas due to the inability of keratoconus to handle reactive oxygen species, resulting in a degradation process that results in corneal thinning and vision loss. […] Keratoconus pathogenesis is heavily influenced by genetics. Some of the origins of genetics include familial inheritance, discordance between dizygotic twins, and other recognized genetic abnormalities. […] In keratoconus-affected corneas, a buildup of cytotoxic byproducts breaks mitochondrial DNA and causes high levels of oxidative stress. The involvement of VSX1 (visual system homeobox 1) and SOD1 (superoxide dismutase 1) in the development of keratoconus is influenced by genetic variables. The most prevalent family keratoconus pattern is autosomal dominant and sporadic. […] Both environmental and genetic factors contribute to the pathogenesis of keratoconus, with eye rubbing being the most important risk factor, followed by allergies and sun exposure.

• #110 Etiology of Keratoconus: proposed biomechanical pathogenesis | In Silico Cell and Tissue Science | Full Text

  https://in-silico-cell-and-tissue-science.springeropen.com/articles/10.1186/2196-050X-1-3

  The etiology of keratoconus most likely involves substantial biomechanical interactions. The goal of this study was to characterize corneal biomechanics using computer modeling techniques in order to elucidate the pathogenesis of keratoconus in biomechanical terms. […] We hypothesize that the etiology of keratoconus could be based solely on substantial biomechanical interactions. It has been previously purposed that pathological changes of the tissue structure might alter the mechanical properties of the cornea, which in turn can affect the gross shape of the cornea under IOP. […] Degradation of the circumferential fibers may very well be an initiating factor of a biomechanical process in which a bulge is gradually created from a presumably healthy cornea under normal underlying pressures and therefore, the identification of the early stages of keratoconus might be achievable by monitoring the in-vivo corneal fiber distribution.

• #111 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Genetic risk factors for KC have proven difficult to identify because of the complex nature of the condition. […] Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC. […] Different approaches have been used to investigate and define the phenotype, mechanisms and causes of KC. […] Observations of corneal changes that occur in KC often do not distinguish between primary changes and secondary inflammatory or degenerative effects. […] Although many differences have been identified that distinguish the KC cornea from the normal cornea, it has not been possible to trace these changes back to primary causes, or to identify the triggers that precipitate the cascade of events that leads to the clinical picture of KC. […] Similarly, a range of suggestive genetic loci and variants have been implicated in the genetic susceptibility of KC, however the current lack of large effect contributions of these loci, SNPs and gene variants suggests a complex aetiology or convergence of multiple disease pathways.

• #112 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Observations of corneal changes that occur in KC often do not distinguish between primary changes and secondary inflammatory or degenerative effects. […] Although many differences have been identified that distinguish the KC cornea from the normal cornea, it has not been possible to trace these changes back to primary causes, or to identify the triggers that precipitate the cascade of events that leads to the clinical picture of KC. […] Similarly, a range of suggestive genetic loci and variants have been implicated in the genetic susceptibility of KC, however the current lack of large effect contributions of these loci, SNPs and gene variants suggests a complex aetiology or convergence of multiple disease pathways.

• #113 Pathogenesis and genetic causes of keratoconus – Shukti Chakravarti Lab

  https://www.shukti-chakravarti-lab.org/extracellular-matrix-changes-and-underlying-genetic-causes-in-a-degenerative-corneal-disease-called-keratoconus/

  Keratoconus is a degenerative thinning and weakening of the corneal ECM, consequent bulging of the cornea with progressive loss of vision. […] While the etiology of keratoconus is not fully understood, interactions of genetic factors with environmental stressors are suspected. […] The pathogenic cellular and ECM changes in keratoconus are increasingly thought to be due to the accumulation of multiple deleterious genetic variants in an individual. […] Additionally, we are studying the transcriptomes and proteomes of corneas in keratoconus subjects undergoing corneal transplantation to identify significant regulatory signaling networks in keratoconus. […] We identified increased expression of stress response genes, while expression of ECM genes, NRF2-regulated antioxidant and tissue-injury response related genes were decreased in keratoconus. […] These studies will identify major genes, biomarkers and pathway that contribute to keratoconus that may be used to improve diagnoses and treatments for keratoconus.

• #114 The pathogenesis of keratoconus

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3930280/

  Genetic risk factors for KC have proven difficult to identify because of the complex nature of the condition. […] Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC. […] Different approaches have been used to investigate and define the phenotype, mechanisms and causes of KC. […] Observations of corneal changes that occur in KC often do not distinguish between primary changes and secondary inflammatory or degenerative effects. […] Although many differences have been identified that distinguish the KC cornea from the normal cornea, it has not been possible to trace these changes back to primary causes, or to identify the triggers that precipitate the cascade of events that leads to the clinical picture of KC. […] Similarly, a range of suggestive genetic loci and variants have been implicated in the genetic susceptibility of KC, however the current lack of large effect contributions of these loci, SNPs and gene variants suggests a complex aetiology or convergence of multiple disease pathways.

• #115 The pathogenesis of keratoconus | Eye

  https://www.nature.com/articles/eye2013278

  Observations of corneal changes that occur in KC often do not distinguish between primary changes and secondary inflammatory or degenerative effects. […] Although many differences have been identified that distinguish the KC cornea from the normal cornea, it has not been possible to trace these changes back to primary causes, or to identify the triggers that precipitate the cascade of events that leads to the clinical picture of KC. […] Similarly, a range of suggestive genetic loci and variants have been implicated in the genetic susceptibility of KC, however the current lack of large effect contributions of these loci, SNPs and gene variants suggests a complex aetiology or convergence of multiple disease pathways.

• #116 Pathophysiology of Keratoconus: What Do We Know Today

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5585454/

  This review will focus on non-syndromic KC, and specifically on our current understanding of the complex pathogenesis of the disease. […] The cumulative proteomic findings suggest a generalized loss of the normal quiescent phenotype of the keratocytes and an increase in the abnormal protein expression, similarly to that associated with wound healing phenotype. The global decrease in different types of collagens is consistent with the clinical observation of debulked and thinned corneas in KC. […] Overall, it appears that KC may be caused by an aberrant tissue response to one or more unidentified stimuli that subsequently leads to keratocyte depletion or dysfunction, loss of collagen, and ultimately a biomechanically weak cornea with a degenerated ECM. […] Altogether, these findings suggest that the TGF- pathway may be an important effector route in KC and warrant further research.

• #117 Pathophysiology of Keratoconus: What Do We Know Today

  https://www.openophthalmologyjournal.com/VOLUME/11/PAGE/252/FULLTEXT/

  This overall pro-oxidative environment was hypothesized to trigger the tissue destruction seen in KC. […] The ECM is produced by keratocytes. This process is regulated, amongst others, by TGF- signaling. […] Altogether, these findings suggest that the TGF- pathway may be an important effector route in KC and warrant further research. […] Overall, it appears that KC may be caused by an aberrant tissue response to one or more unidentified stimuli that subsequently leads to keratocyte depletion or dysfunction, loss of collagen, and ultimately a biomechanically weak cornea with a degenerated ECM.

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