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The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease

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The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease Adv Ther (2019) 36:2205–2222 https://doi.org/10.1007/s12325-019-01026-0 REVIEW The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease Eleftherios Loukovitis . Nikolaos Kozeis . Zisis Gatzioufas . Athina Kozei . Eleni Tsotridou . Maria Stoila . Spyros Koronis . Konstantinos Sfakianakis . Paris Tranos . Miltiadis Balidis . Zacharias Zachariadis . Dimitrios G. Mikropoulos . George Anogeianakis . Andreas Katsanos . Anastasios G. Konstas Received: June 11, 2019 / Published online: July 30, 2019 Ó The Author(s) 2019 ABSTRACT abnormalities primarily relate to the weakening of the corneal collagen. Their understanding is Introduction: Keratoconus (KC) is a complex, crucial and could contribute to effective man- genetically heterogeneous multifactorial agement of the disease, such as with the aid of degenerative disorder characterized by corneal corneal cross-linking (CXL). The present article ectasia and thinning. Its incidence is approxi- critically reviews the proteins involved in the mately 1/2000–1/50,000 in the general popula- pathophysiology of KC, with particular tion. KC is associated with moderate to high emphasis on the characteristics of collagen that myopia and irregular astigmatism, resulting in pertain to CXL. severe visual impairment. KC structural Methods: PubMed, MEDLINE, Google Scholar and GeneCards databases were screened for rel- evant articles published in English between January 2006 and June 2018. Keyword combi- Enhanced Digital Features To view enhanced digital nations of the words ‘‘keratoconus,’’ ‘‘risk features for this article go to https://doi.org/10.6084/ m9.figshare.8427200. E. Loukovitis K. Sfakianakis Hellenic Army Medical Corps, Thessaloniki, Greece Division of Surgical Anatomy, Laboratory of Anatomy, Medical School, Democritus University of E. Loukovitis Á N. Kozeis Á A. Kozei Á E. Tsotridou Á Thrace, University Campus, 68100 Alexandroupolis, M. Stoila Á S. Koronis Á P. Tranos Á M. Balidis Á Greece Z. Zachariadis Á G. Anogeianakis Ophthalmica Eye Institute, Vas Olgas 196 and D. G. Mikropoulos Á A. G. Konstas (&) Ploutonos 27, 54655 Thessaloniki, Greece 1st and 3rd University Departments of Ophthalmology, Aristotle University, Thessaloniki, Z. Gatzioufas Greece Augenklinik, Hornhaut, Katarakt und Refractive e-mail: [email protected] Chirurgie, Universitaetsspital Basel, Mittlere Strasse 91, 4031 Basel, Switzerland G. Anogeianakis Association for Training in Biomedical Technology, A. Kozei Aristogeitonos 6, 54638 Thessaloniki, Greece School of Pharmacology, University of Nicosia, Makedonitissis 46, 2417 Nicosia, Cyprus A. Katsanos Department of Ophthalmology, University of E. Tsotridou Á M. Stoila Ioannina, Ioannina, Greece Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece 2206 Adv Ther (2019) 36:2205–2222 factor(s),’’ ‘‘genetics,’’ ‘‘genes,’’ ‘‘genetic associa- Scholar and GeneCards databases for articles tion(s),’’ ‘‘proteins’’, ‘‘collagen’’ and ‘‘cornea’’ related to KC. The keywords used were ‘‘kera- were used. In total, 272 articles were retrieved, toconus,’’ ‘‘risk factor(s),’’ ‘‘genetics,’’ ‘‘genes,’’ reviewed and selected, with greater weight ‘‘genetic association(s),’’ ‘‘proteins,’’ ‘‘collagen’’ placed on more recently published evidence. and ‘‘cornea’’ and all their relevant combina- Based on the reviewed literature, an attempt was tions. The search focused on articles written in made to tabulate the up- and down-regulation of English from January 2006 until June 2018. A genes involved in KC and their protein products total of 177 articles were identified and and to delineate the mechanisms involved in reviewed, and both their text and references CXL. were analyzed. The analysis of these references Results: A total of 117 proteins and protein revealed an additional 95 relevant articles, classes have been implicated in the pathogene- which were also subsequently reviewed. The sis and pathophysiology of KC. These have been current article is based on previously conducted tabulated in seven distinct tables according to studies and does not contain studies on human their gene coding, their biochemistry and their subjects or animals performed by any of the metabolic control. authors; its aim is to summarize current Conclusion: The pathogenesis and pathophys- knowledge on the proteins involved in KC. It iology of KC remain enigmatic. Emerging evi- also represents an attempt to map and catego- dence has improved our understanding of the rize the proteins that are up- or down-regulated molecular characteristics of KC and could fur- in KC according to their corneal stromal ther improve the success rate of CXL therapies. location. Keywords: Collagen; Corneal biomechanical characteristics; Corneal cross-linking; CXL; RESULTS Ectasia; Keratoconus proteins; Ophthalmology Histopathology, Biochemistry and Biomechanics of KC Corneas INTRODUCTION Histologically, KC is characterized by degrada- Keratoconus (KC) is a corneal dystrophy that tion of the basal membrane of the corneal seriously affects the quality of life of KC patients epithelium, diminishing of the number and [1]. Its prevalence ranges between 1/2000 and density of collagen fibrils, thinning of the cor- 1/50,000 in the general population. The condi- neal stroma, and keratocyte apoptosis with tion is characterized by moderate to substantial necrosis [2–4, 9]. Keratocyte apoptosis and visual impairment due to the development of necrosis involves the central anterior stroma corneal protrusion and thinning [2–6]. In KC, and Bowman’s lamina and, typically, weakens visual acuity decreases due to progressive myo- the corneal tissue [12, 13]. Slit-lamp examina- pia, irregular astigmatism and, often, corneal tion reveals subepithelial and anterior stromal apical opacification [4, 6, 7]. The key underlying scars [14] due to degeneration of epithelial basal factor for these pathological changes is weak- cells, as well as fine folds in the posterior stroma ening of collagen tissue in corneal stroma [6, 8]. at the corneal apex (Vogt’s striae). Endothelial Although KC is generally a bilateral disorder damage is rarely visible. The presence of Fle- [2, 9, 10], rare unilateral cases have also been isher’s ring, which is formed by the accumula- described [11]. tion of hemosiderin around the base of the corneal cone [2, 15], is also frequent. In con- trast, breaks of the Descemet membrane with METHODS subsequent leakage of aqueous humor into the corneal stroma, leading to corneal edema and The present review is based on literature search decompensation (acute hydrops), are rare. that utilized the PubMed, MEDLINE, Google Finally, evident corneal nerves together with a Adv Ther (2019) 36:2205–2222 2207 decrease in sub-basal nerve density are promi- hydroxyproline concentrations [23]—an indi- nent features of advanced KC [2, 15, 16]. cation that the alteration of corneal biome- The stroma in KC is characterized by a chanical properties in KC are the result of decrease in the number of collagen lamellae and collagen cleavage into smaller peptides [23]. a reduction in the amounts of microfibrillar and This conclusion is further supported by the fine granular material [17]. Changes are also observation that the solubility of pepsin-treated observed in the arrangement of fibrils of the collagen from KC corneas is greater than that anterior stroma [15, 18], together with abnor- from normal corneas—apparently due to the mal distribution of collagen fibers. This results breakdown of KC corneal collagen into smaller in the decrease of corneal mechanical resistance peptides that has already occurred [23]. [15, 18]. Overall, the thinning of the corneal stroma Collagen itself is associated with keratocyte apoptosis, alterations in the extracellular matrix (ECM), The amount of collagen, which is a major cor- and changes in the activities of several enzymes neal protein [2, 24, 25], is reduced in KC [12, 19] that involve the activation of degrading [12, 26]. The decrease in collagen types I and III enzymes and the promotion of cell death, both is related to alterations in the ECM basement of which are mostly due to oxidative stress membrane [26], while the decrease in collagen [20, 21]. Although the mechanisms of tissue type IV is related to alterations in the basement breakdown remain obscure [21], over the last membranes, of which collagen type IV is the 25 years there has been strong evidence that major structural component [24, 27, 28]. In collagens are susceptible to oxygen-free radical addition to the decrease in the amount of col- damage [20, 22]. In addition, collagen is the lagen in the cornea, the shape and transparency only protein susceptible to fragmentation by of the cornea also change due to re-orientation superoxide anions, a process during which of the collagen molecules and fibrils [29, 30]. small 4-hydroxyproline-containing-peptides are The combination of changes in collagen orien- liberated [20]. In the presence of oxygen, tation and the reduction of total collagen con- hydroxyl radicals cleave collagen into small tribute to corneal thinning in KC [30]. peptides; the cleavage is, apparently, specific to Type IV collagens are major structural com- proline or 4-hydroxyproline residues [20]. In ponents of basement membranes and consist of contrast, hydroxyl radicals, in the absence of six proteins encoded by six genes (COL4A1– oxygen, do not induce fragmentation of colla- COL4A6). Interestingly, these genes are orga- gen molecules, but they trigger the polymer- nized in pairs
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