Abstract
Collagen crosslinking provides the mechanical strength required for physiological maintenance of the extracellular matrix in most tissues in the human body, including the cornea. Aging and diabetes mellitus (DM) are processes that are both associated with increased collagen crosslinking that leads to increased corneal rigidity. By contrast, keratoconus (KC) is a corneal thinning disease associated with decreased mechanical stiffness leading to ectasia of the central cornea. Studies have suggested that crosslinking mediated by reactive advanced glycation end products during DM may protect the cornea from KC development. Parallel to this hypothesis, riboflavin-mediated photoreactive corneal crosslinking has been proposed as a therapeutic option to halt the progression of corneal thinning by inducing intra- and intermolecular crosslink formation within the collagen fibrils of the stroma, leading to stabilization of the disease. Here, we review the pathobiology of DM and KC in the context of corneal structure, the epidemiology behind the inverse correlation of DM and KC development, and the chemical mechanisms of lysyl oxidase-mediated crosslinking, advanced glycation end product-mediated crosslinking, and photoreactive riboflavin-mediated corneal crosslinking. The goal of this review is to define the biological and chemical pathways important in physiological and pathological processes related to collagen crosslinking in DM and KC.
Highlights
Collagen is the most abundant protein in the cornea and comprises roughly one-third of total protein content in the human body [1]
type 2 DM (T2DM) showed a protective effect against KC development
diabetes mellitus (DM) is associated with increased advanced glycation end product (AGE) that lead to inter- and intramolecular crosslinking and formation of AGE adducts on long-lived proteins, such as collagen and elastin
Summary
Collagen is the most abundant protein in the cornea and comprises roughly one-third of total protein content in the human body [1]. The expression and organization of collagen and the extracellular matrix (ECM) within the cornea are highly regulated processes coordinated to maintain the structural, mechanical, and refractive properties of the tissue. Tissue-dependent expression of specific collagen isoforms and proteoglycans influence a tissue’s biomechanical properties, i.e., stiffness and elasticity, based on fibril size and organization. The dominant collagen isoforms present in the human corneal stroma are heterotypic fibrils of collagen types I and V [2] and small amounts of types VI, XII, XIII, and XIV, among others [3,4]. Descemet’s membrane is predominately composed of type VIII collagen [5] with the epithelial and endothelial basement membranes composed of type IV collagen [6]
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